Good evening everybody and welcome to this webinar vet presentation tonight. My name is Bruce Stevenson and I have the pleasure of chairing tonight's webinar. Little bit of housekeeping before we get started.

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Back to tonight. We are very lucky to have Matt Gurney with us tonight. Matt graduated from the University of Liverpool back in 2003 and he spent several years enjoying mixed practise before returning to Liverpool to undertake a residency in anaesthesia and analgesia.

Since 2009, he has worked at North West Veterinary Specialists, which is a multi-disciplinary specialist hospital in Cheshire. Matt himself is a European veterinary specialist and an RCVS recognised specialist. Matt, welcome again to the webinar vet and it's over to you.

Good evening everyone, and this evening we're talking about new drugs and new ideas on old drugs. So this is the 2nd webinar in this series. We started with talking about human factors and safety, so if you missed that one, that's a great one to catch up on.

And then we'll be back with the next two in the session later on, in the summer. So tonight, most of the advances that I'm going to talk about relate to drugs, specifically, and actually of all of those drugs, the vast majority of them relate to analgesia. And I guess that's really good news because for our patients, we really want to be able to advance our analgesic practise.

We'll look at some longer term options and the other options we're gonna look at are acute pain options as well, so a bit of a mix. So getting started off. I think we're fairly familiar with new non-steroidals appearing on the market.

And I've just got this picture here of all of the ones that we have available in dogs at Northwest. I just went to the pharmacy and took this selection out. I'm sure you all have your preferences from a non-steroidal point of view in dogs and in cats as well.

And I think when we're prescribing nonsteroidals, we think about what we like about non-steroidals. We have a very good idea as to the efficacy of non-steroidals in the acute management of pain and also in chronic management of pain for conditions such as arthritis. We're very familiar with the response that we get from non-steroidals.

We're also very aware of the safety precautions that we have with this group of drugs and things that we should be thinking about, things we should be warning owners about. Unfortunately, sometimes we do experience adverse events with non-steroidals, and most common adverse event is vomiting, as we know. We can see diarrhoea, and we can see some more serious adverse events such as hemorrhagic gastroenteritis.

So yes, we have a class of drugs here that, We know a lot about. They have a predictable efficacy, but also we we have some adverse effects that we maybe make them unsuitable for certain candidates. So we're looking for something that offers us the analgesia provided by these drugs, but hopefully.

With a reduction in adverse effects, it's always the same with any drug we use, there's gonna be an adverse event effect and how do we minimise that. We're very familiar with how non-steroidals work. They inhibit the cyclooxygenase enzyme in the arachidonic acid cascade.

That in turn reduces production of prostaglandins, prostacyclins, and thromboxanes, the inflammatory mediators that activate, stimulate the nooceptors to transmit, initiate the transmission of that painful stimulus first to the spinal synapses and then to higher centres where we have pain perception. We're very familiar of the anti-inflammatory effect that these drugs produce in the periphery. And of course we are very familiar with the reduction in prostaglandins they cause.

That has a cascade effect. If we can control prostaglandin production, we reduce the downstream production of other inflammatory mediators such as bradykinin and a whole host of other contributors such as histamine. Having said we're familiar with how these drugs work, we know they are prostaglandin antagonists.

There is a new molecule. It's, the generic name is grappyran, the trade name is Galipran. This is a drug that's been licenced in the US.

It was licenced last year in the US, so we have a little bit of experience coming across the pond about using this drug. And you will see, if you read the vet record or or any of the veterinary magazines, you'll see this drug has got a European licence now. And we're expecting it to be released in the UK later in the year.

Now it, it is a prostaglandin antagonist, but a very specific prostaglandin receptor. You see right at the bottom of this slide here, we've got the EP receptors. So it's an EP4 receptor antagonist.

And what it's doing is blocking prostaglandins at a much more specific point further down that arachidonic acid cascade. You can see on the right hand side of this diagram where corticosteroids act. You can see where non-steroidals act.

This is acting much more further down that cascade, specifically at this receptor responsible for pain and inflammation. So again, another drug with a real targeted approach. The hope is always that if we can target receptors specifically responsible for a certain effect and we're not blanket inhibiting prostaglandins, then maybe we'll be able to spare some of those prostaglandins that have some of those regulatory housekeeping functions, such as preservation of blood flow to the gastric mucosa.

What we're looking for here is a drug that provides analgesia like the non-steroidals, but with a reduction in adverse effects. You can access all of the licencing studies. If you just do a PubMed or a Google Scholar search for Grappyrant or Galiprant, you will find the licencing studies, and Galiprant has a canine licence.

It's licenced for pain and inflammation associated with osteoarthritis in dogs. And it's a daily oral tablet. And from the licencing studies we know that safety and efficacy has been documented.

And this is just one of those studies here, so it was a prospective randomised placebo controlled multi-site study of grapiran in dogs with documented osteoarthritis. And we had two groups, there's the the dogs receiving grapiran at 2 migs per kg once daily versus dogs receiving a placebo. We've got quite a large number of dogs in this study, 285 dogs, and these researchers looked at pain scores using the canine reef pain inventory.

Now that's a pain score that is validated for assessment of arthritis. It splits, it's, it's only completed, it's split into two sections, so it's got the 1st 4 questions which are directed at how painful does the owner feel that their dog is? And the next 6 questions are assessing how that pain interferes with the dog's daily activities.

You then have a section which is asking the owner to complete, to make an assessment of what the dog's quality of life is. So you see, the first section scored about 40, the second section scored out 60, overall scored out of 100. Some people will then index that, so you get a score out of 10.

But it's a validated outcome measure for a study of this type, we're dealing with a chronic condition. Other outcome measures were examination by the vet dealing with that case. And of course the licencing study, they're going to look at clinical pathology work as well, so routine haematology biochemistry.

Looking at these graphs here, these are looking at these two different sections of the, the CBPI. So the top graph is the pain severity score and the bottom graph is the pain interference score, and how those change. The graphic print versus that placebo, the placebo being the open circles on the top line and the graphy prank group being the, the black dots.

The little stars next to the black dots mean that each time point taken there, so when they assess these dogs every 7 days for 28 days, there was a statistically significant difference in all of those scores, so the pain severity score and the pain interference score at every time point over the course of that study. What they did notice in that study was obviously they're they're looking for adverse effects. What they interestingly noticed in the placebo group was that a significant proportion of dogs in the placebo group experience vomiting.

When they compared that to the Galyrant grab your Prant group, they noted that, Dogs vomited to a very similar degree on the medication versus a placebo, so dogs tend to vomit, they don't tend to vomit anymore when receiving this medication compared to a placebo. Obviously what we're really looking forward to now is a study, a published study documenting use of grey brand compared to a non-steroidal. So that's that work has been done, we're just waiting for publication of that.

So where does it fit, if we're thinking, OK, this is launching later in the year, which of my cases am I gonna think about using this on? Is this a first line drug, so a dog that I see and I think, well normally I would prescribe you a non-steroidal, but should I prescribe grappiran instead? I think right now it's probably quite a difficult question to answer and.

What we're really relying on here is some of that experience from the US suggesting whether we should start with this or we should start with a non-steroidal. If you have a case that you administer a non-steroidal to and they have an adverse reaction, what do we normally do? What do we do now?

We, of course, stop the non that non-steroidal. Personally, I then try another non-steroidal because we, we don't really know why dogs react adversely to one non-steroidal versus another. Interesting just to have in our heads that placebo group that vomited when they were given a placebo pill as well.

So is there a factor there? We've always got to gauge how severe that, that vomiting reaction is if we're taking vomiting as that reaction. I tend to try another non-steroidal.

Like I say, which one you start with, which one you switch on to, there's no evidence that one non-steroidal is more safe or efficacious than another, but I know we all have our personal experience about which one we find that we see fewer adverse effects with. I think now we probably have a drug that in the studies that have been conducted, there, there were studies conducted in the states for licencing, there have been some studies conducted in Europe for the European licence. We now have a drug that we can say this is non-inferior to a non-steroidal from an efficacy point of view.

So what you could expect is I have prescribed a non-steroidal to my patients. My patient has experienced an adverse effect with that, so I want to stop the non-steroidal. I'm now going to start prescribing rapids.

I should expect a similar degree of analgesia from the grey to the non-steroidal. So at the moment, what you're hearing me say is we don't have superiority evidence and you don't really have to prove superiority to gain a licence for that drug. So those studies that have been done so far are non-inferiority studies.

So we think these drugs provide a similar degree of analgesia. What we're hoping to see is a reduction in the, the side effects associated with grappi brands. I'd be really interested actually, once this is launched just to hear from you and see how it's influencing your prescribing of non-steroidals.

Are you using grappire as that first line drug or are you still using non-steroidals as your first line drug? We said before, didn't we? OK, what else do we do if we feel that we can't use non-steroidal.

The other situation we're often in is we prescribed a non-steroidal and we need to add something else. I thought this was, this is quite an opportune time while we're talking about new drugs and old ideas and new ideas on old drugs, just to reconsider the Tramadol story so far, because this is an emerging story really, and there are a few different opinions out there and more and more studies. This was one of the first studies that actually wasn't really set out to document beneficial effects from tramadol is actually comparing Carprofan, our test drug, to this, sorry, Carprofan, our reference drug to this TRIP V1 antagonist test drug.

Not quite sure why they threw tramadol in there as another group in these dogs, but there were 49 dogs with osteoarthritis and Each, each group receives either carrofen or tramadol or the trick view one antagonist experimental drug or a placebo. The outcome measures physical exam, the can and brief pain inventory score again, activity monitoring, gait analysis and rescue analgesia. So quite a comprehensive range of outcome measures for dogs with osteoarthritis, which I think we would think are probably appropriate measures to use in patients that we would see on a day to day basis suffering with arthritis.

I pulled out the significant results from this study here. What they noted from the K and pain inventory scores were was that mobility was improved with carrofen and tramadol. However, the interference and severity scores were markedly more improved with carprofen, which is what we'd expect.

Like I say, we know what effect to expect from our nonsteroidals. They did however note that a treatment effect was seen in all groups. So we're seeing a little bit of a placebo effects coming through that.

And I think we should accept that a placebo effect is normal for the vast majority of long term or chronic analgesia trials. With regards to the use of rescue analgesics, so do they have to intervene to improve comfort in those patients? There was a decreased use of rescue in the Carrophan group.

Again, exactly what we'd expect of Carrophan. When they scored activity, there was no, no statistically significant difference in any group, but in the cart prove there was an increase in daytime activity, again, exactly what would, we would expect. The conclusion from the study was that the test drug was unfortunately not as effective as corofen or tramadol for treating hip arthritis.

So yes, thumbs up there for Carrafen. This was the one of the first studies that said, well, maybe there is something going on there with the tramadol, maybe the tramadol is effective for these cases. What we also need to consider as a confounder there is that placebo effect, that presence of the placebo effect.

So that was using a population of dogs with chronic pain. This is a study using a population of dogs with surgical pain. And OK, these were dogs were undergoing tibial plateau level in osteotomy, so you could argue.

How chronic their pain was if they've got injuries to the cruciate ligament, but they run again surgery. So an acute pain stimulus. And I think this study tried to answer the question, OK, fine, I'm giving the dog a non-steroidal, but I want to give something else cos I don't think that's enough post surgery to keep my patients comfortable, and I think we probably all think that.

So if you compared erroox previco to tramadol. To a combination of both of those. There were 10 dogs in each group, the outcome measures they use were pain scores in those patients for 24 hours after the procedure, and an assessment of how they use their limbs.

And I think we probably expect we're going to see a greater effect in the combination group. When he looked at using the Glasgow pain scale as their outcome measure and asking the question how many dogs are scoring higher than 6 out of 24, which is the intervention level on the Glasgow pain scale, the level at which you say I need to provide more analgesia. In the Previcock group, Ferrococcy group, 4 out of 10 dogs fell into that category.

In the tramadol group, we've got a much higher number of dogs falling into that painful category. And look at the combination group. We would expect fewer dogs to be in that category, wouldn't we, but we've got a number sort of in the middle there.

So we're not actually seeing that analgesic advantage. When we look at more painful dogs, so the dogs scoring 8 out of 24 on the Glasgow pain scale, and I think you've got to be pretty painful to score 8 out of 24. In the erroco subgroup, 11 dog fell into that category.

In the tramadol group, 4 dogs fell into that category. In that combination group, perhaps there is a little bit of an advantage there. The conclusions that they drew were that the pain scores were higher in the tramadol group versus the ferrocoa group and there was a greater use of rescue analgesia in the tramadol group.

So this study isn't really documenting a beneficial effect to tramadol. So we started out with an inkling from that previous Malec study saying, oh look, maybe there is something in Tramadol. The investigators in this study are saying, well, tramadol's no better than a non-steroidal alone.

This is a more recent study published this year, and I think it's a fairly opinionated title to this paper, lack of effectiveness of Tramadol, the Treatment of pain. So you can see someone's trying to prove a point here, and the opener in their introduction is, well, there's been a lot of CPD recently, and lots of online people, suggesting that we should be using tramadol in dogs, so we're here to to almost set the story right. The design of the study was a randomised blinded placebo controlled crossover study, so each dog, each arthritic dog received each treatment.

So they had tramadol, then they had a washout period, then they may have got placebo in a wash up period or Carrofen. The outcome measures that they used were gait analysis, looking at the vertical impulse and the peak vertical force, so they're looking at how much weight these dogs are putting on their affected limb. And again they use the canarepa inventory score as an outcome measure there.

What they were able to show with the force plate analysis, but there was no change from baseline peak vertical force or vertical impulse in the tramadol or the placebo group. But they did show significant changes with carprofan. So again, Cartpraffe is our reference drug, we expect, we give the dog a nonsteroidal and it reduces its lameness, dog's more comfortable, it's gonna put more weight on that limb.

And of course they also noticed significant improvement in the Canari pain inventory scores with Carproffe. Carprofen was actually one of the tests drugs used to validate the Canonri pain inventory. And the conclusion that these guys drew was that data from their present study provided no support for the use of tramadol in dogs with osteoarthritis of the elbow and the stifle joints.

So again, we're not really seeing much support in the literature for the benefit of Tramadol in our osteoarthritic patients. We can take a sympathetic balance view on this. There are some people that say tramadol just doesn't work and we should stop using it.

There are others that say, actually in chronic pain, there is something there that Tramadol is helping these patients with, these dogs with. We think it's potentially treating the suffering element of chronic pain. I think we all have cases where Tramadol, we think Tramadol works, the owner thinks tramadol works, or the owner says, I, I never want to use tramadol again in my dog.

The the most important thing is if we're going to use Tramadol, we need to be upfront with the owners and say it may work, it may not work in your dog, and you've got to tell me if you don't think it's working because we'll find something else. Personally, Tramadol isn't a great first line drug for me in osteoarthritis in any chronic pain. I don't tend to prescribe it as my second line following non-steroidals.

Yes, that's the topic for another webinar and I, I, there's a webinar under my biography on chronic pain, so if you want a little bit more information on what your second line drug would be, I take a look at that. And this is a statement from a survey on analgesia of small animals that when. Vets were surveys regarding their analgesic prescription habits, habits, that's not really the right word, is it?

The analgesic pres prescribing. Compared to Association of Veterinary anaesthetists members. Increased proportion of non-AVA members, so people with less of an interest in anaesthesia and analgesia perhaps, reported that they did prescribe Tramadol.

Compared to AVA members, fewer AVA members, obviously, more interest in analgesia, maybe a little bit more of awareness on this topic, fewer of those prescribing tramadol? And of course I think I fall into that category. I think there are better options for us than Tramadol.

But if you've already got patients that are on Tramadol and you think it's working, then of course I would advise you continue. So that's the tramadol updating dogs. This is the tramadol updating cats.

So really until I read this paper, right, in my opinion was well. Doesn't make a massive difference in dogs, so does it actually make a huge difference in cats? I guess the other thing I'm not a massive fan of tramadol in cats is we don't have a great formulation to administer cats.

We have to give capsules or tablets, we don't have a liquid option. This study here looked at the use of tramadol for the treatment of osteoarthritis in elderly cats. It was a randomised crossover study, and it looked at cats older than 10 years old, there were 24 cats.

They had radiographic evidence of osteoarthritis on an examination they had evidence of pain associated with osteoarthritis and limited mobility. The outcomes that they used were they use an activity monitor on each cat, and the owners scored the impairment, the degree to which their activity was impaired over the course of that study. What they wanted to look at were different doses, and so they had a placebo group, they had a 1 meg picking, 2 meg picking, a 4 meg picker group, and they prescribed the tramadol twice daily.

And each cat went through each dose, so they had 5 days of treatment and at the weekend they didn't receive any treatment, then on the Monday they switched on to the next group in a randomised order. So quite a clever study design really. The main outcome that they noticed was that there was a significant increase in activity in the 2 meg per kg group versus the placebo group.

They didn't see that effect in any of the other doses, the 1 or the 4 meg per kg. And significantly more owners consider their cats to be improved in that. So we add about 2 meg per cake dose.

So remember these owners. One week the cat got 4 gigs per gig, 1 week it got 1 mg per gig, 1 week it got placebo, 1 week it got 2 mg per gig, so the owners were actually able to compare how their cat was on those different doses, which obviously they were blinded to. In the study overall, 85% of owners considered the quality of life to be improved during the study.

So that's a fairly high number, we can see some of that placebo effects coming through. You give an owner a pill for their pet and they want it to make it, want to make the pet better. One of the comments, even at that 2mg per kg dose, so actually your take home here is, OK, 2 migs per gig does improve activity in those cats, and the owners considered them improved.

But there were some cats that experienced side effects. So I think we've all heard these reportsed from owners. The cat looks a little bit spaced out.

They have crazy episodes where they run around a little bit more, or they just sleep very well, or they sleep a lot more. My advice would be to start those cats on a dose of 2 mg per gig. In this study, you see they were administered that dose for 5 days, so we're looking for a response within 5 days.

But we're saying to the owners, if you think your cat needs less because they're a little bit of spaced out, they experiences some side effects, then we know what we're going to do, which move we're going to make next. So I hope that gives you a little bit of insight into where we're up to with Tramadol overall and the differences that we see between dogs and cats. And really these differences are down to metabolism.

We traditionally learned that tramadol has opioid effects, it's a new agonist, but it also has noradrenaline and serotonin effects. In dogs, potentially, the opioid effect is quite minimal. Because we know that the opioid effect is due to this intermediary metabolite, the or the active metabolite, the odes methyl tramadol, those aren't great at creating that metabolite.

In cats, tramadol has a very a much higher bioavailability, so actually that 2 mg per kg in a cat is potentially a greater dose than 2 migs per kg in a dog. And cats clear tramadol quite slowly, so in dogs, people were saying, well, for Tramadols to be effective, you probably have to give it 4 times a day. In that study where they documented that benefit, they give it twice a day in those cats.

And when I say it may play a role in reducing central sensitization, this is potentially what we refer to as treating that suffering element. So a few new insights on tramadol. I feel we're still in a bit of a watch this space situation and we will see more on Tramadol in the months or years to come.

Another drug that we're quite familiar with using, and actually this is less from an an anaesthesia and analgesia point of view, rather than a a a perioperative care point of view. There's a study published mid last year looking at the effects of administering gabapentin prior to a veterinary appointment on signs of stress in cats. And I think we'd always question what are we actually doing with those cases?

Is this genuinely reducing anxiety or is it just sedating the cat? And the difference there, well, I think it's still up for debate, what's sedation and what's angiolysis. In this study they used a single pre-appointment dose of 100 milligrammes, so one capsule of gabapentin, and the owners scored how stressed they thought their cats were.

And the vet scored how compliant the kitties were. Both of these scores were significantly lower when those cats received gabapentin. Now a 100 milligramme for a your average count isn't really 5 kg, is it anyway it's more 3, 3.5 to 4, so that's a pretty big whacking dose of gabapentin.

And in our experience, we tend to use this for cats that are coming back on a repeated basis for to see our oncologists for chemotherapy, just to reduce any anxiety associated with placing that IV administering that chemo. And we find it chills those cats out really nicely, but we don't tend to use such a high dose. So for your average size 3, 3.5 kg cat, we will use 50 milligrammes.

A bigger cat, you may want to use a 100 milligramme capsule. When they start talking about non-steroidals and what to do when we can't use non-steroidals, we generally end up talking about paracetamol, so this seems a a sensible webinar to talk about a drug that's been around for a very long time. And has been licenced for a very long time, but I think we, we, we went out of favour of using Pardale, and we've started using a lot more in the past 10 to maybe 15 years.

Is it a non-steroidal? How does it work? And we're gonna talk about acute and chronic use of paracetamol.

The doses illustrated there in the BSAVA formulary for both paracetamol as an IV preparation and PardoLV as an oral preparation, and if you're familiar with this, you'll appreciate there is a difference in dosing. So we end up with this dose range of 10 to 33 mg per kg. Now the 33 mg per gig is the dose on the pardale.

10 mg per gig, nobody really knows where 10 mg per gig came from. That's the dose listed in the BSAVA formulary. If I'm using intravenous paracetamol, and you can buy generics, the one on the screen here, Perthalcon is another one that you can get from your veterinary wholesaler.

I'll use 10 gigs per gig, IV 3 times a day. The licence dose in dogs is 33 MB per gig, IV 3 times a day. We worry about paracetamol and liver.

Just because we're using a drug that's metabolised hepatically and at very high doses can cause hepato toxicity doesn't mean that at therapeutic doses we're going to cause any degree of liver damage. So we shouldn't worry about causing liver damage with paracetamol. I think paracetamol has quite a bad rep for that.

I tend to use paracetamol where we have a patient that is concurrently receiving steroids. Patients, dogs that are non-steroidal intolerant or maybe we've tried another non-steroidal, that's just not an option. Patients with Pyrexia, paracetamol's a really good antipyretic and of course we're never gonna use paracetamol in cats.

For a drug that's been around such a long time and is actually licenced, we would probably expect a little bit more evidence. But unfortunately we don't have a whole heap of evidence in dogs that regarding paracetamol's analgesic efficacy. This is something that we looked at a couple of years back, asking the question, are our patients that we give paracetamol to as comfortable as the patients that have a non-steroidal?

And we did this by looking at hospital records from patients that couldn't have a non-steroidal for their stifle surgery versus patients that receive meloxicam as a routine for the stifle surgery. We looked at pain scores overnight in those patients following surgery, and we looked at how much methadone we were administering to those patients because we were pain scoring and giving methadone as required. And what we did notice is that the dogs in the paracetamol group weren't significantly more painful and didn't require significantly more methadone than the non-steroidal group.

And this really, this is a little bit of internal audit for us, it answered our question, when we can't use a non-steroidal, we give paracetamol and we think those patients aren't as comfortable. So I'm not saying you should use this as a replacement for non-steroidal cos obviously non-steroidals are licence, intravenous paracetamol isn't licence. Of saying that where you can't use a non-steroidal, then we have a very good second option here.

Paracetamol's not really cast as a non-steroidal anymore because it's anti-inflammatory effect is really weak and it doesn't really have a significant peripheral anti-inflammatory anti-prostaglandin effect like the non-steroidals do. The analgesic effect is blocked by serotonin antagonists, so it probably plays a role in sending inhibition, this top down inhibitory effect from the brain down to the dorsal one of the spinal cord, putting the brakes on that incoming pain stimulus. And we also know from studies that it requires intact cannabinoid receptors for its action, and cannabinoid receptors are located in the dorsal or of the spinal cord.

And one of the intermediary metabolites of paracetamol activates central transient receptor potential for van aloid receptors. So you can see there are a lot of receptors that paracetamol acts on. So maybe rather than searching for the one receptor that paracetamol works on, we should accept that it's probably it's own multimodal analgesic.

If we talk to our human colleagues, they say, well, you don't know exactly how it works, but we know it works. And it acts on cyclooxygenase 3 centrally. So you'll see most of the actions of paracetamol are actually central rather than peripheral.

It's working at the level of the spinal cord. Moving on to another drug that you've been licenced for many years and we all have ketamine sat on the shelf in the practise. I think one of the most common questions I get is, OK, fine, in the UK we're talking.

I open a bottle of ketamine and in a one man practise, two man practise, it goes out of date before the end of the 28 days that I'm allowed to keep that ketamine open. My answer to that is I have a lot of ways to help you use that ketamine. Yes, we don't use ketamine so much for induction of anaesthesia anymore.

We rarely use ketamine as an induction agent in dogs in the UK. Still use in conjunction with diazepam for dogs in, in a variety of countries around the world. You may feel familiar with using ketamine in a triple combination for cats, but that's probably the most common use in practise.

We're using ketamine more and more now for analgesia versus it's anaesthetic effects and at much lower doses. So we know ketamine is an excellent analgesic, but we don't need to use it at your 5 MB per kg dose that we are familiar with for induction to see those analgesic effects. A very low dose and this is all quite anecdotal at the moment, there's, there's nothing really published on this.

Is 0.5 mg per gig subcutaneously for chronic pain cases. Ketamine's an NMDA receptor antagonist, and this is a receptor in the dorsal of the spinal cord responsible for central sensitization.

So it's a great target for our chronic pain cases. And for your next chronic pain case, And I've used this mostly in dogs. If you're struggling with a patient, you think actually you're really painful.

I prescribed a non-steroidal. I'm gonna add something else, but what else can I do? Try half the magpicocoketamine subcutaneously.

And experience teaches us that we can repeat that as required. And I've had cases that receive that on a monthly basis or a two weekly basis or a weekly basis depending on their comfort levels. That's talking from a chronic sense.

From an acute sense, again, we talked about the NMDA receptor. This is a receptor becoming active when we have long standing or very intense pain. And of course a lot of our surgical patients may have long standing pain.

They probably have central sensitization already and we're looking at using something alongside our opioids and our nonsteroidals in a multimodal fashion to provide analgesia. Ketamine as a continuous rate infusion makes perfect sense for that. And the rate I use is 5 to 10 mcg per kilo per minute.

Pretty easy. Once you've worked the maths out, an easy way to use the ketamine is to take 1 mL of ketamine, bearing in mind ketamine is 100 mg per mL. You put your 1 mL of ketamine in a 100 mL bag of saline, and it makes a solution of 1 mg per mL, and that makes your maths really, really easy.

You can run that through a drip pump or a syringe driver. This works beautifully in painful cats after surgery. So if you've got a cat and you've given them an opioid, you've given them a non-steroidal, and then they're still painful in the recovery period, you think, what am I gonna do now?

Getting the CRI at 5 mcg per kilo per minute is the answer to that problem, and you will get a very happy cat. Works incredibly well in dogs as well. So this is a great way to provide your patients with excellent pain relief and use your ketamine up as well.

And those are those rates that I've just mentioned on the screen there. Other types of analgesic. Drugs that have been around for a very long time, lidocaine, we have been using local anaesthetics in veterinary anaesthesia and pain management for many years.

With advances in opioids and non-steroidals, our use of local anaesthetics declined somewhat, but this is something that's really on the rise now and gaining a huge amount of popularity. There's some great evidence in dogs that we see a marked reduction in opioid consumption with a successful local anaesthetic block. When we pain score those patients in the recovery periods, they have much lower pain scores compared to us using an opioid CRI.

And our options that we have are lidocaine, buppivocaine and ropivicaine. Lidocaine, short onset, shorter duration of action up to 1 to 2 hours, buppivocaine and ropivicaine, both of these are lasting 68, potentially 10 hours. So we've got some good options here for acute pain management.

Why are we talking about local though, what's the future? Is there anything new on the horizon? Well, this is the new drug that's been licenced in the States, which again is probably gonna come to Europe in the later half of this year.

This is a lipozo encapsulated buppihocca. And by encapsulating that local anaesthetic in liposomes which degrade slowly once injected, we can prolong the duration of action of that nerve block. Up to 96 hours.

The product is called Noitta, and if you do a search online for Noitta. You will find you'll come across a YouTube video, so I start with YouTube and you'll find a video that shows the use of this drug. Now it's licenced for infiltration of wounds postoperatively.

So you just see on the right hand side of the screen here, this is just the technique whereby you infiltrate that incision. You've got your fascia layer, you've got the deep subcutaneous infiltration, and you've got superficial subcutaneous infiltration as well. So we're depositing our local at all layers of the incision.

So just have a look at that video, and it'll show you exactly how that's used. It's licence at the moment is just for infiltration of incisions and obviously when you licence a drug and give a drug to anaesthetists, they look at a variety of different ways of using it. So this again is going to be a watch this space case, but I would advise you stick to the licence recommendations if you're starting using this drug when it becomes available.

Back to anaesthetic drugs, just to wind up with. Oh excellent. Alfaxolone is licenced as Alfaxan now.

I'm sure some of you were familiar with a product called Saffan which was alfaxolone aladolone. And what we didn't like about saffan was the solubilizing agent because it caused adverse reactions in dogs and histamine release in cats. This newer combination of afaxolone brings some of the things that people did like about saffan, and saffan you could use intramuscularly because of the absorption characteristics of this molecule.

Now obviously alfaxin is licenced for intravenous induction of anaesthesia, that is its licence indication in dogs, cats and rabbits. Like I say, you put a drug on the market and people start thinking, oh, actually, can I use this in cats and exotics that I previously relied on saffron for. And if you do a public med search of intramuscular alfaxolone, you'll come up with over 50 hits of papers that people have documented use of different combinations in a variety of species.

Now I think probably the most useful intramuscular use for day to day practise in dogs and cats is the use of IM alfaxone for cats. This particular study looked at it in combination with dexamedatomidine and methadone at those doses, so fairly familiar doses, good analgesic doses for surgery there. And they had dexamed methadone, the ketamine, or dexamed methadone and alfaxolone.

Now 3 migs per gig is quite a high dose of alfaxolone. And really the thing that limits our IM use are is obviously big volumes. Personally, I don't tend to use more than 2 migs per gig of alfaxolone, but I'm just putting this study up here as an example.

Their outcome measures were need for additional anaesthesia in each of these two groups and the need for rescue analgesia. And of course recovery characteristics. Between those two groups, the additional anaesthesia and analgesia provided was similar.

Probably because the analgesia is coming from the methadone and the dexammeatomidine, remember alfaxolin doesn't have any analgesic properties. The recovery was better with alfaxolone compared to that ketamine group, and I think we're all familiar with the recoveries we see with that kind of dose of ketamine in cans. Oh.

We see back to that, oh sorry, that final slide there. I think this is one of those drugs that is best used in combination with another drug, and that study illustrates that quite nicely, that if you use it in combination with alpha twos, then you can see a quite nice sedative effect. The other drug that I've used it in combination with is midazolam.

So 1 to 2 mg per kg of alfaxan with 0.25 mg per kg of midazolam as a combination using intramuscularly for those cats with sus that you're suspicious of cardiac disease, but you just can't get any of those cats. You need to give these cats something safe in order to sedate them.

The other option with alfaxan is a subcutaneous use as well, and that's been examined at a dose of 2 to 3 mg per kg, subcutaneous alfaxan in conjunction with 0.3 mg per gig of butterphenol. And again, if you do a public search, you'll find that study as well.

And just to finish, I'm just gonna touch on the alpha 2. I'm not gonna go through everything associated with alpha 2s, but there seems to be more of a, a trend for people moving away from ACE chromazine towards alpha 2s. So we know what we like about the alpha 2s, excellent sedation, balanced anaesthesia, multimodal analgesia because these are analgesics as well.

They're antagonnizable after a certain period of time. And of course titratable, so if we give an alpha 2 and we don't see the effects we want, we can top that dose up. We don't like the bradycardia we see, but we know why those cases develop bradycardia.

This is normal for alpha 2 agonists. We see a mild hypertension. That's because of the action of the alpha 2 receptors on blood vessels causing vasoconstriction.

This is a really common misconception. The first thing we see when we give an alpha 2 is the blood pressure increases. Eventually over time as the alpha as the alpha 2 wears off and perhaps our patients under anaesthesia with a volatile agent like Io or Sivo, over time, that blood pressure may decrease, more likely in dogs rather than cats.

Cats tend to, to keep quite an acceptable blood pressure under anaesthesia. That's not time dependent, whereas dogs you tend to see a mild hypotension develop. So it's just important to have those, those differences in your head there.

Hypertension, which is mild, followed eventually by hypotension. We know that sometimes the alpha 2 effect can wear off, we don't like that. And if we give the alpha 2 without an opioid, we can see aesis.

There is another drug on the market, there's meatomidine, Domitor which we're all familiar with, and Dexedatomidine, Dexommatol. Now metatoidine is two isomers, so it's got levo and dextro isomers in there. The levo is inactive, it doesn't do anything.

The dextro is the active component which accounts for all of the sedative and the analgesic effects. If you'd like to read a little bit more about it, I'd recommend this review at the bottom of the screen here. This is an excellent review, incredibly comprehensive on the cardiovascular and and antinosusceptive properties in dogs.

So it's really only the dextro component that's doing anything, which is the theory behind moving on from meatomidine to Dexedlaomidine using the purer isomer. The theory being that the purer drug has a greater effect with a reduction in side effects. It's probably not strictly true from a sedative effects point of view.

Dexamedatomidine seems to offer profound sedation, which is dose dependent, but it potentially doesn't last as long as that of meatomidine. So that levo meatomidine probably is influencing how that dextromeatomidine is metabolised. If we look briefly at the effects we see, we administer these drugs.

This is looking at heart rate changes, with different doses of alpha 2, and we can see, we see this acute decrease in heart rate after administering the drugs and that wears off over time, which is dose dependent. You see a similar effect in blood pressure, you'll see I mean arterial pressure starting here in these dogs at 130, 140, increasing higher in the higher dose groups. Decreasing over time, and this graph here is illustrative of meatomidine on its own administered IV in dogs.

And those of you will note that these dogs are never actually becoming hypotensive. The mean arterial pressure is never going below 60. So that's a nice graphical illustration of what our blood pressure does after we administer alpha 2s.

I'm gonna skip over a systemic vascular resistance index is a measure of vasoconstriction. So actually when we give these drugs are. Vasoconstriction is increasing, that's what's increasing our blood pressure, and again you can appreciate that graphically what happens over time at different doses.

And cardiac index, we know because these drugs cause a bradycardia, they reduce our cardiac output. There is also some reduction in contractility. These are the reasons we don't like using alpha 2s in patients with cardiac instability, because we see this marked reduction in cardiac output, which our fit and healthy patients can tolerate, but our compromised patients can't.

Now all these slides that I've just presented to you are meatomidine work. We don't have a comparative work for Dexedatomidine. My clinical impression is that the effects that we see with Dexedatomidine are more mild compared to meatomidine.

That doesn't, however, give me the confidence to use them in cardiovascular compromised patients. So in our fit and healthy patients, we see less of the bradycardia. We see probably a similar degree of vasoconstriction.

We see that nice increase in blood pressure that we like with alpha 2s. We talked about bradycardia, we've talked about hypertension, we talked about vasoconstriction. These are important things to recognise when we're monitoring alpha 2 anaesthesia.

We need to remember that when we switch our volatile agent on the I or the requirement will be markedly reduced. But we said before that these drugs can wear off quite quickly, oralitus can wear off quickly in dogs, and so we should monitor our patients very closely and we should have a plan in case that dog does come light under anaesthesia. For those of you that are sat there thinking, well, I use aromazine or I use alpha 2 agonist and I can't draw, I can't remember the comparisons between the two, I just put this table in here for you to just review that's got the differences between those drugs, and you can review that at your leisure.

I think the final thing that we're going to look at tonight is related to anaesthesia. This is another paper that I picked out of veterinary anaesthesia and analgesia from 2017. I get lots of questions about Meropotent, Cerenia, Prevamax, can we use it as an anti-nausea drug?

So POMV stands for post-op nausea and vomiting. This is a question that this study set out to examine, and they use a population of dogs undergoing ovarian hysterectomy, trying to document A, can we document post-op nausea and vomiting in these patients? And they concluded that yes, they documented post nausea and vomiting in up to 50% of their cases.

The question then being, does Mropotin at the time of pre-medication reduce the incidence of that? Interestingly, they noticed in the Murropotin group there was a lower isofluorine requirement in those patients. We don't have any concrete evidence at the moment that mropotin is an analgesic, although based on its mode of action, potentially it could be.

Between these groups, the researchers were unable to document any differences in post-op nausea and vomiting, so we can't definitively answer that question at the moment. I think in a lot of our patients that we may be dealing with that are quite sick, they may be receiving more anyway, and I think that I personally think there's an advantage there for improving comfort in those patients. So What I did when I started researching this lecture, I took the most recent journals and I looked at things that I felt were significant changes, new drugs that I think you should know about, and just an update on where we're up to with some drugs that we're very familiar with using.

And so that's a fairly comprehensive review for you of where we're up to. If you've got any questions related to that, I'd be happy to answer some of those questions. Of course, I, I made references to quite a few sources of information there, so please do feel free to follow those sources of information.

Matt, that was fabulous and it's so nice to have such a a concise synopsis of these drugs that we very often take for granted and we know they work, but we sometimes forget why they work or how they're working. So thank you very much for that. It's much appreciated.

Great. Matt, something you were talking about was the, the use of paracetamol. And you were saying paracetamol together with non with steroids.

And the use of paracetamol as opposed to or in comparison to non-steroidals. But what about combining paracetamol and non-steroidals? Yeah, I do that quite commonly, in two, I'll give you two examples, one acute one chronic.

And we, we occasionally have patients that have been through surgery, they've had methadone. They've had a non-steroidal and when we examine we think you're just still a bit uncomfortable, I've given you quite a bit of methadone and I can't give you any more non-steroidal, so what shall I do? And in those cases, there's dogs, you give them 10 mg per gig of paracetamol IV and you go back half an hour later and it definitely improves their comfort.

I, I say definitely, that's purely anecdotal, it's quite a common practise in our hospital to do that. We don't have any, any publications on that, something to work on. From a chronic sense, I will often add in pardale to a dog receiving non-steroidals.

If they, we think, OK, you're in your non-steroidals, we accept that there's only so much non-steroidals can do. Arthritis is a progressive disease. We're always gonna get to the stage where we need to add in something with our non-steroidals.

I think pardale's a sensible second line in those dogs. And in those cases I do use it at the label dose, I'll do that for 5 days because it's, it's licenced 33 MBs per gig 3 times a day for 5 days. And then beyond that, we're off label, so we're having a discussion with the owner and saying, well, have you noticed the difference?

Let's carry on at that dose. I know some people though that will say, well, I'm just gonna use 10 migs per cake. You've got to ask the question whether that's effective and, and I think the cane and Brief pain inventory is a really good tool to use.

You can download that if you just search for it, download a copy, but I would recommend you use that for your, your owners when you're managing these cases and judging your interventions. Excellent. You talk about Pardale.

I know Pardale is our only licenced product. But what is your feeling about using, human paracetamol? I mean Pardale, you're going off licence after 5 days anyway.

So if you're discussing off licence with the owners, there's a feeling of, you know, Padale's got all the wrong ratios between its components and that's the thing. So why not just go for straight paracetamol from the beginning and use it at 10 megs per gig. Yeah, absolutely, that, that's definitely an option as well, and we've got plenty of clients that some, I think it's quite rare to see adverse effects with Parder, but I have seen them.

And in those cases we use 10 mg per kg of paracetamol, and I do know people that will increase that to 20 mg per gig of paracetamol as well, so you've got some options to, to explore there in those cases. Yeah, I, I just, the 33 meg per gig just scares the living daylights out of me, I have to be honest. When you were talking about the use of ketamine subcut, for chronic pain and that sort of thing, this variable interval of once a week to once a month.

Do you also, and Sally's asking, do you also find that you get, injection site pain or pain at the, the, when you're injecting it subcutaneously? I've I've never seen pain on injection, although I mean any dog, I think you get a reaction to injection, don't you? On that repeated administration, I, I haven't seen dogs resenting that repeated administration, and I, I had someone ask me a couple of weeks ago, well, have you ever used this once daily?

I had an owner that, she works at a vets, and her dog with chronic pain, he was, he had ketamine every other day, and that did help. So, on a, I know other people are using ketamine at at that frequency in a more palliative sense. I, some people say, well, if you're gonna start doing it, do it for 5 days.

And some people say, well, try it at monthly intervals to start. So again, we know this works in some patients, but we don't have the exact answer as to what the frequency should be. So I would judge it based on the individual case, to be honest with you, to start with.

And start low and build it high rather than the other way around or start high and taper it off. Holy, I start 0.5 a meg per kg with that frequency of monthly intervals and then.

You're gonna repeat it in those owners that notice a difference, and then they're gonna know when their pet's comfortable and when it starts wearing off, so it's really one for the owner to judge how frequently they feel their pet needs it. And going back again to the multimodal approach, you would put that on top of the non-steroidal and the paracetamol. Yeah, absolutely.

I've got no qualms about using ketamine alongside other drugs, non-steroidals, paracetamol. Yeah. Excellent.

It's all about the patient and how comfortable they are, especially in chronic pain cases. That's the bottom line, isn't it? Yeah.

Matt, that was absolutely fabulous. Thoroughly enjoyed it and so nice to touch back on these drugs and to, to hear about some new ones that are coming as well. And although it's it's still wait and see or watch the space.

I think you said, it's really great to have somebody with your expertise and your level of knowledge sharing with us. So thank you for attending the web bringing this to us that we can attend such a great . Session of lectures from you.

Thanks everyone for joining in. Right, everybody, that's it from us for tonight and hope you enjoyed it as much as I do and we look forward to seeing Matt again. And remember that Matt has got a lot of other webinars that he's recorded that you can go back and look at and trust me when I say they really are worthwhile.

So from my side and from the webinar vet, it's good night to everybody. Thank you.