Good evening. So tonight we're going to talk about some of the mechanisms of chronic pain, and this almost follows on from some of the webinars that we did later last year. So if you want some references on some of the other things, then I'm going to direct you to part of the chronic pain series that I did last year as well.

And those of you that joined me last year will probably recognise this statement that I'm gonna start with. Which says that the numerous mechanistic differences of the maladaptive responses to deal with the pain represent a major obstacle in the development of novel and effective medications. Now in that previous webinar we talked about some of the analgesic options that we have, and I'm not going to dwell a lot tonight on analgesic options, so please refer back to that.

But now we're going to focus on some of these changes that are occurring and what we know from a mechanistic point of view. And what we call the maladaptive response because really chronic pain is a maladaptive response. It serves no genuine, logical purpose, and we have a problem to deal with, and that is pain.

So, as well as the physiological mechanisms that we'll talk about, there are some risk factors that we need to discuss. And of course, if we fail to address these, these will affect our treatment success. I will go through the physiological aspect.

So we'll take this from The nociceptor up through the neuron to the dorsal horn of the spinal cord. And we'll talk about those mechanisms and where exactly they're happening. And throughout the webinar we'll draw on some principles of treating chronic pain.

So yes, as I said, we've got to address all of these matters equally, more important, in order to give us the best chance of successfully treating that patient. Looking at these these risk factors. This is a statement that I think is incredibly useful that says the pain is a subjective sensation that cannot be attributed only to the incoming no susceptive information.

And what do we mean by that? Well, We've got to think about the psychological aspect of what's going on. We've got to think of any social factors associated with the patient, and we need to think about some physiological factors to understand.

And I'm going to give you an example of each one of these and why they seem to be important in the treatment of our chronic pain cases. Regarding psychological factors, we know there's a wealth of literature in the human field looking at depression and anxiety and how they are major contributors to pain. This paper that I've referenced at the bottom of the screen here, this is just starting to shed some light on whether we can look at a negative effective state in our veterinary patients.

And they've been able to do this with Cavalier King Charles Spaniels with syringa myelia. So they were able to show that that negative effect of state, so being in pain does create a negative effective state, and it changes the dog's outlook on life. I don't know if any of you suffer from chronic pain or you know people that suffer from chronic pain, but it certainly changes your outlook on life.

And these are some quite clever studies looking at a positive reward. So there were 5 food bowls and the dog was blinded to which one contained food and which one didn't contain food, but when you release the dog from a certain point, they soon learn which bowl contains food and which bowl doesn't contain food. And they soon realise .

And if there's a bowl that has food in, the dog's gonna move quicker towards that bowl versus a bowl that doesn't have any food and the dog's not gonna move so quickly towards that bowl. And when they measure the time taken for the dog to get from that, that standard point to the bottle, it's a lot slower and those dogs with a negative effective state. So the dogs in pain with the syringomyelia have that negative effective state.

And the other aspect of that, they looked at rewarding those dogs for running to the bowl with a treat. And if when the treat diminished in size, you could see a much more marked reluctance to run to the bowl in those dogs with with syringomyelia. So It's quite a simple but also quite a clever way of documenting this that shows a clear difference.

So dogs in chronic pain do have this negative effective state. There are some social factors to think about and I think we can all think of cases where behaviour interacts strongly with interpretation of pain, treatment of pain. This makes me think of a little dog that I treated in the last year, who, she was a little shih-tzu, suffering from hip dysplasia.

And the first response, of this dog when I called the owners into the consult was that for the dog to hide under the chair. And the owner said, well, that's just normal for her. That's what she does.

We've got, I can't remember is it 3 or 4 dogs in the house, and she's at the bottom of the pecking order. And to me, there's a clear behavioural problem within that group of dogs and talking to the owners. I explained that it would be very difficult to gain out of control of that dog's pain whilst there are still those social factors.

So these cases certainly require input from a behaviourist, and I would encourage you to grow some links with your local behaviourist, if you are treating these types of chronic pain cases. Physiologically I guess in the job that we do, we work long hours, we potentially work late nights. We know how sleep quality impairs our ability to perform, but we also know there's a huge body of literature showing that sleep quality effects and impairs pain inhibitory mechanisms.

Now I make this a question that I ask all of my owners at the first consult in chronic pain cases, asking them how well does your pet sleep? Does your pet's pain affect their sleep quality? And I guess the answers are almost a little bit disappointing kind of first time round, but this is a question that I would encourage you to ask owners repeatedly because what you will find is that as you treat those patients successfully, Then the quality will improve.

And one of the things a lot of clients say following acupuncture is that the patients sleep quality markedly improves. They'll go home after the acupuncture and they'll sleep all afternoon, and then they'll sleep much better in the days and nights, after those acupuncture sessions. To make it something that you ask on the first consultation.

We also consider reasking that question to get an understanding of whether your analgesic intervention has helped to improve that patient's quality of life. Now, This slide is a result of Google search. When I put in the term, it's not how bad the pain is, it's how the pain makes you feel.

What we're talking about is the effective state, so how the pain makes you feel. And that's really what we're trying to get a really good handle on in all of our patients is not how painful they are, but what's the impact of the pain on that patient's day to day activities. And I really like a lot of these the things that this search rew up.

And thinking about that pain and the type of pain that generates those negative effective states, we're generally thinking about inflammatory pain, neuropathic pain, and cancer pain. Inflammatory pain at the top of the list there. We know that the vast majority of our chronic pain patients, dogs, cats, rabbits are suffering from inflammatory pain of osteoarthritis.

Neuropathic pain, a little bit more of a, a difficult one. Perhaps some of our patients that are suffering from spinal pain. A great example would be the Kavvala King Charles we referred to with syringomyelia, a classic example of neuropathic pain there.

And of course, we will deal with patients suffering from cancer pain. In all of these there's a lot to think about and I'm going to start with looking through some of those origins of pain and digging into some of these underlying mechanisms to give a greater understanding of what we're actually trying to treat here. So we're gonna follow the pain signal from the periphery to the central nervous system, considering what's going on at the nose receptors, what neurotransmitters are involved, what's going on in the primary neuron.

Through to the dorsal ganglion where the cell body of that primary afferent neuron is, dorsal horn, where that primary afferent is synapsing into the central nervous system and considering the ascending pathways to the, the cortical region, and then the descending pathways, the top-down projections which can modulate that signal at the dorsal horn of the spinal cord. Something you may be familiar with, but I thought it's worth reminding everybody because I mentioned it quite a lot, are these two definitions, allodynia and hyperalgesia. And we see these with both peripheral and central sensitization.

So allodynia is a painful response to a non-noxious stimulus. So in this dog, normally running a bit viro down the dog's anti-braium shouldn't be perceived as a painful stimulus. This dog has a brachial plexus neoplasm and perceives a normal stimulus as a painful stimulus because of that old sensual processing.

Hyperalgesia is the second term, and that is defined as an exaggerated response to noxious stimulus with a widened receptive field. So if we say a dog has cruciate disease, it has inflammation in that joint, it's got a painful joint, we would expect that index joint to be painful. What we wouldn't expect unless we have altered central processing, sensitization, we wouldn't expect other joints on that same limb to be affected.

But this is what we do see with certain chronic pain states. So you see a spreading of this receptive field. So areas that you wouldn't expect pain from suddenly start transmitting the signals that are perceived as pain.

Quite a lot taken on this schematic here of a no receptor. There's a lot going on. I've seen plenty of diagrams of no receptors with Illustrations of the receptors and of the inflammatory mediators.

We've got some that we may recognise. We've got bradykinin, the interleukins that we recognise as inflammatory mediators. Hydrogen irons, ATP.

And we've got a lot of receptors there, cytokine receptors, we may recognise some of these sodium channels. I quite like this diagram because it shows the interaction between the nose receptor and what's going on from a vascular point of view as well, and you can see some of these immune cells coming in. So you're already seeing the crossover between pain processing and the immune system, and there is more and more crossover that we now know about between these two systems, but not two completely distinct systems.

The process that we talk about the What's occurring at thenoceptor is known as transduction, so converting that inflammatory stimulus into something that the neuron can transmit to the dorsal and spinal cord. We're talking about transduction here. And taking osteoarthritis as our example of chronic pain, we have inflammation within that joint.

We've got peripheral sensitization. There may be joint instability if we to cruciate ligament disease as an example. There may be bone bony changes causing subchondral bone pain.

There may be swelling, distension of the joint capsule. Ligamentous disease certainly causing instability, and we've got a synovial fluid full of inflammatory mediators causing that pain and that lameness. There's definitely peripheral sensitization here.

We're gonna look at central sensitization as well. The mechanical factors, ligament disease making the joint weak. The inflammatory factors within the synovium, we have a whole variety.

We've got nerve growth factor. Now that sensitises certain types of receptors and that increases the number of ion channels in the nose receptor. So another example of increasing the receptive field.

And we know in osteoarthritis, there's an increase in, in NGF in the sin of fluids. There are these compounds called damps, the damage associated molecular patterns. Those are released by damaged cells.

So if we have cellular damage, we're going to see an increase in these within the joint. And they also occur where cells there's where there's exhalation of plasma proteins into the joints as well in those inflammatory conditions. Those cause cytokines.

And there are examples of sites that you'll be familiar with interleukin 1, interleukin 6, tumour necrosis factor, those directly sensitise the most receptor. So we're definitely not talking about one. Compound here, we're talking about a whole variety of inflammatory components.

I know we're very familiar with talking about prostaglandin, and I haven't many prostaglandins yet because we're familiar with nonsteroidals and nonsteroidals work. Prostaglandins also sensitise the joint and they cause the release of all of these other components. We've got calcitonin gene-related peptide, that's another neuropeptide that causes vasodilation and what we call neurogenic inflammation, which we'll come back to the explanation of.

Due to all of this, we have a greater neuronal response and the recruitment of additional nose receptors. So these additional nose receptors are increasing the traffic up to the dorsal horn of the spinal cord, but there's a greater input. And we get activation of specific no receptor channels as well.

This is all peripheral sensitization, sensitization going on in the periphery. When I said about recruitment of other nose receptors, these are known as silent nose receptors, so they're C fibres, they're recruiting inflammatory conditions. Normally they're silent, but they're activated by a very high threshold.

So when we have these inflammatory states, they're activated by that intense stimulus. They enhance the receptive field of the central nervous system. You're probably sat here thinking, well, why do we need to enhance the receptor field?

And we've already talked about the illogical nature of chronic pain. Acute pain serves a function, so you could argue that in the acute phase, yes, there is a function to alerting the body to how much this hurts, but there isn't much of a function to this 3 month thing. 10 months down the line.

And we're creating hyperalgesia here. Everything that's going on peripherally on the left hand side of the screen here. Is fueling the fire essentially and on the right hand side here we've got the dorsal horn.

So this on the left is the primary afferent neuron that's the terminal. The main neurotransmitter here is glutamate, acting on AMPA or NMDA receptors, and we'll come back to NMDA receptors. You can see there are opioid receptors.

So we know that if we use opioids in these painful patients, this is where the opioid receptors are acting to reduce to modulate that signal. We've got some CB receptors, those are cannabinoid receptors. Potentially one of paracetamol's mechanisms of action is working on cannabinoid receptors, and this is probably where it does that.

The other cells we've got here, microglial cells and astrocytes. We'll come back to those because previously we understood that microglial cells and astrocytes are just supporting cells in the DNA, but there is actually more of a role of these cells in pro-inflammatory states. Peripherally, we saw on that noceptor terminal, some of those sodium channels and there's a channel called Eri V1, so transient receptor potential vanoloid.

Centre. Now these respond to heat and acid can say the, the components of chilli peppers. The iron channels, so they transmit sodium and calcium.

And by activating these channels, they transmit the pain stimulus through these transmitters called substance P and calcitonin G related peptides, which you've already seen. Both of these have receptors at the dorsal horn of the spinal cord. And there are your receptors peripherally and centrally.

The relevance here is that we know that TripV1 receptors are up regulated in osteoarthritis in both man and dogs. Do we think conventional analgesics can deal with blocking these channels? I guess if we can find an agent that could selectively block sodium and calcium channels, then we might be onto something.

Some of the agents that we do have in our armoury, such as lidocaine, we know block sodium channels. So potentially this is why there's an argument for lidocaine as a continuous rated fusion in those cases of particularly bad osteoarthritis where we can't find anything else to control the pain. That increased expression of TRV1 receptor.

Within the joint further causes releasing inflammatory mediators, substance be acetagen-related peptide. So again, what they're doing is just potentiating that signal. So peripheral sensitization is driving further release of neurotransmitters at the central level that plays a key role in allodynia.

In studies where people look to trip B1 antagonists, because this channel is sensitive to heat, one of the problems with giving these antagonists, orally, is that, one of the side effects is hyperthermia. And so there's a study looking at administering those drugs inarticularly in order to avoid those side effects. And this is an area of current research, so quite exciting.

So far we've mentioned neurogenic inflammation and we've mentioned substance being calcitany gene-related peptide, and so you can see how all this is coming together now. Neurogenic inflammation is where activated nose receptors release further inflammatory mediators. And now that definitely sounds counterintuitive, doesn't it?

We thought the nose receptors transmitted that painful stimulus from A periphery to B, the dorsal horn of the spinal cord, but now we're saying actually they're actually stimulating release of further inflammatory mediators, which definitely doesn't make sense. This is one of the best diagrams that I've found. This is from Stephen Fox's book called Pain Management in Small Animal Medicine, which is a fantastic book.

And it's got that lovely diagram of the activated nose receptor triggering the release of further inflammatory mediators, causing vasodilation, plasma extravasation, liberation of sensitizers. The stimulating that notice. So this is all periphery mediated for driving central sensitization.

And when we look at the science behind this, then there are certain disease states migraine, interstitial cystitis, osteoarthritis, inflammatory bowel disease, and asthma, where it's documented that neurogenic inflammation is actually driving this. So you can see here, this is going back to what we said about the crossover between the immune system and the pain transmitting system. We typically think of something like inflammatory bowel disease as an inflammatory immune-related condition, don't we?

But there's this component of neurogenic inflammation, so crossing over between these two areas. So in all of our painful cases, we should think is peripheral inflammation a driver? We may not be thinking about our classic heat swelling redness when we think about peripheral inflammation.

There's enough evidence in osteoarthritis that the level of inflammation you get is that peripheral driver. But neurogenic inflammation produces peripheral sensitization, and we have a whole load of receptor upregulation going on. So in these cases, we're just feeding the central nervous system.

This is just driving central sensitization. So the take home really is to control periphery. For pain, peripheral inflammation as well as possible to limit that drive to central sensitization.

Think about analgesics. Clearly our first line analgesics are the non-steroidal anti-inflammatories. There is a role for sodium channel blockers here.

There are a lot of different sodium channels, lots of different subtypes of sodium channels, and lidocaine is not particularly specific. So the current drive at the moment is to try and find specific sodium channel blocking agents. So let's move a little bit further up that pathway to the dorsal root ganglion.

So this is where we said the cell body of the neuron sits. And we know that in patients with peripheral sensitization, we see an increase in calcium channels here. And we know that gabapentinoids, gabapentin pregabalin work on the alpha 2Delta subunit of the calcium channel.

So potentially this is where our rationale for using the gabapentinoids in treating this type of pain lies, where we have a peripheral driver causing central sensitization, and certainly I've used gabapentin in quite a number of osteoarthritic patients to good success. Let's not just think about gabapentin as being a a drug for neuropathic pain. You can see when you understand a little bit more about the mechanistics of this, you start to maybe expand your repertoire, or if you're already using it, you understand exactly why you're using it.

Moving up to the dorsal horn. See, the dorsal horns arranged in these lovely Rexta lamina, and we have C and A delta fibres synapsing in layers 1 and 2. Layer 2 is also known as the substantial gelatinosa, where the opioids work and a lot of our other analgesic drugs are working.

So this area receives our peripheral input. And here we have either excitatory or inhibitory into neurons which either increase or decrease that signal. We have the NMDA receptor, which some of you and they will be familiar with.

There are trippy1 receptors here. This is the site of activation of descending modulation, and we will come to descending modulation and we'll also mention glial cells as well. So dorsal horn synapses.

We've got this input. If we have uncontrolled input, then this is another area where the receptive fields can be increased. The periaqueductal grey mat, so the osteoventral medulla and the locusulus are all higher centres, so they're located centrally within the brain, and they're part of this top down system.

When we have a lot of activity at the dorsal and the spinal cord. This affron activity that we talked about, it can trigger long-lasting excitability. The process is central sensitization.

What we see is a reduction in thresholds required to activate that input into the central nervous system. So the example would be that dog with a brachial plexus lesion where we said a big biro is stimulating that dog and causing pain. Now if I run a biro down my arm now, it doesn't cause me any pain at all.

That dog has central sensitization and these mechanisms. There's an increase in responsiveness. You see prolonged aftereffects as well, so.

That initial pain, if you have a patient with central sensitization and you inflict the painful stimulus on them, it will last for a lot longer than a normal painful stimulus would do. Central sensitization is defined as augmented sensory signalling, an increase in sensual excitability, as well as a loss of inhibitory control. And as before, we mentioned, we see allodynia and hyperalgesia with it.

So just think which of our patients have central sensitization? Is it the 12 year old arthritic Labrador? Is it the dog with an osteosarcoma?

Is it the dog with intervertebral disc disease? Probably all three of these have central sensitization. They have peripheral pain of a chronic duration, which is enough to drive those sensual changes.

So let's think a little bit more about central sensitization in our everyday patients. It's not some, this isn't a textbook diagnosis. This is something that you'll see tomorrow.

From a human perspective, we've talked a lot about peripheral mechanisms, obviously, you can demonstrate central sensitization in human volunteers and certainly osteoarthritis is, again, the biggest category in people of central sensitization. And we know this paper I quote at the bottom here. This is a literature review looking at a whole vari variety of different pain conditions.

And they say that in osteoarthritis, that central hyper excitability plays a significant role. In dogs, this can be documented as well. And there are certain tests that you do called quantitative sensory testing QST.

Where you can evaluate dogs with arthritis and documents that they, they have a greater response to these tests. The first being the pressure algometer. So you apply a force to a joint or another painful area, and when the dog turns its head to react, then it gives a force read out at the point at which the dog reacts.

The second device is called a von Frey filament. There's a set of filaments and with different pressure, you see a bending of the filament. If you apply the first filament and it bends and the dog doesn't react, you go up to a thicker filament and you keep going until you find a filament where the dog reacts.

If you do this in dogs with arthritis versus dogs that don't have arthritis. The first two, at the top, EVF, that's the von Frey filament, and the second one down PA that's pressure algometer. You can see here I stands for index joint, T was tibia.

M was metatarsal, say the index joint was the stifle where these dogs were painful, and the tibia and the metatarsals were areas where they didn't expect to find pain. But what they were able to show was that the dogs that didn't have arthritis, obviously they had a greater tolerance for pressure and the von Frey filaments compared to dogs that had arthritis, and the same was true in those other joints. So yes, you would expect that index joint to be painful, but the dogs with osteoarthritis in one joint, of course we know that.

You probably have arthritis in a variety of other joints, but this also serves as evidence of hyperalgesia, so widening of that receptive field. These dogs are painful in areas beyond the main area of pain. And this study is quite nicely documented that which concurs with that human work.

You can see that these baseline. Studies are actually not very important for then evaluating any further analgesics. So yes, they're useful to us on a day to day basis to show that our osteoarthritic patients do indeed have central sensitization, but more importantly, if we're looking at, let's say evaluating a new drug, maybe one of those sodium channel blockers, we want to be able to test that very rigorously and make sure it does exactly what we hope it's going to do for our patients.

The conclusion from that paper was that long-standing osteoarthritis and associated pain. Increased should increase the matters sensitivity, which is inferred to be at least in part due to central plasticity. So what are the mechanisms that we're looking at here, we've talked also about central sensitization, what's actually causing it?

There's NMDA receptor activation. There's activation of microglia and astrocytes, and what we refer to as inflammation centrally. So as well as what's going on in the periphery, all of that inflammatory soup, there's a lot of inflammatory inflammation and inflammatory mediators working essentially at the level of the dorsal horn.

So our NMDA receptor is located at the dorsal horn. Under normal circumstances, pain is transmitted. We already said that this is a glutamate receptor.

Pain is transmitted via a receptors. If we have intense or chronic pain, then we see upregulation of those receptors. We see an increased conductance through those channels, and we see hyperpolarization of that secondary neuron.

What happens when you get hyperpolarization there is this magnesium plug that sits in the NMDA channel gets knocked out. And so this NMDA channel is therefore open. And By transmitting through the NMDA channel, we have a much more responsive way of transmitting pain up to where it's perceived as pain in the cortex.

So this is one of the key mechanisms that we know quite a lot about for central sensitization. So really our aim with excellent pain management is to either prevent activation of this receptor or to close that receptor by using analgesics. One of the analgesics we're most familiar with that we use in an acute sense is ketamine.

Ketamine is an excellent NMDA antagonist. And all NNDA antagonists that we use for chronic pain are amantadine, memantine, and you'll find more information about those in that previous webinar. Microg and astrocytes, we previously understood that these were supporting cells of the central nervous system.

This supported the neurons. But actually, we now know that they are modulated stenosis action. There's some very good evidence that where you have a neuron activated, the neuron then expresses a protein, and that protein then activates the astrocytes and the microglia.

This activation can occur within 24 hours and it lasts a week. This gives them a role in maintenance of that hypersensitivity. And contributes to hyperalgesia and allodynia.

Secondary to that, they then stimulate further release of pro-inflammatory agents. So quite an interesting discovery back in 2003, this paper was produced and gives us another target for drug discovery, looking at targeting these astrocytes and those microglia, preventing their activation and looking at what we could do to minimise the response once they are activated. So what analgesics do we have for sensitization?

We have touched on two mechanisms NMDA, astrocytes, microglia. We mentioned TRIPV1 receptors previously, and the fact that they're located centrally, and we mentioned calnogen-related peptide and cannabinoid receptors as well. Of course, I'm gonna say we should avoid or we should treat those peripheral causes.

NMDA antagonists are particularly useful and we have those available at our disposal in veterinary practise. Opioids, we saw that there are opioid receptors essentially, so it certainly makes sense to use our opioids. Gabapentinoids.

Paracetamol because of the way paracetamol acts on those cannabinoid receptors. And There's a lot in the news at the moment about the use of cannabinoids for a whole variety of conditions, and you can understand the rationale behind that for pain when we understand some of these mechanistic functions of cannabinoid receptors. So we do actually have quite a few options for treating sensual sensitization at the moment.

The final mechanism that we're going to look at is descending modulation. And this is really a top down system. So think of it as a damper or a break on the CNS input.

Remember we said at the dorsal horn that a signal can either be augmented or inhibited. Well, this is one of the inhibitory systems and it's mediated by serotonin and noradrenaline. We know that the alpha 2 agonists, meatomidine index meatomidine, they act in the locos erulus, and this is probably the mechanism by which they produce analgesia.

We know acupuncture activates the descending modulatory system as well. Some antidepressants, we know that antidepressants are used in chronic pain in people, obviously for their antidepressant activity, but potentially there is some effect on the noradrenaline serotonin, particularly the serotonin system in descending modulation and the influence that they may have there. So there are a number of agents that activate the system.

In people where tramadol is effective, this is probably how tramadol is working as well, the the noradrenaline serotonin effect. Potentially, I know we, we think of Tramadol as an opioid agonist, but probably the opioid system isn't the most effective. There's been a lot of work recently in the acute sense suggesting Tramadol is not particularly useful.

If it is working in those dogs, this is probably how it is working. They As I said, a top-down system that just puts the brakes on that incoming signal is almost a decision maker there saying, am I going to transmit this painful stimulus up to the foulus in the cortex and let the pain perception through, and this is just slowing down that input there. One more thing to consider, damaged nerves, of course, we talked about neuropathic pain, and we typically think about neuropathic pain being caused by lesions affecting the somatosensory system.

Where we have nerve damage, we can see ectopic activity, so either spontaneous or evoked. So activity that can occur at rest, causing pain at rest, which sounds like a pretty awful situation to be in. We know where we have nerve damage, the sadium channels cluster around that damage, increasing that input into the central nervous system.

Where we have nerve damage and you have nerve growth factor, you can see cross excitation where fibres that previously transmitted touch start to transmit pain, and that's probably what's happening in the, the example I gave the dog with the brachial plexus lesion. We've got that cross excitation, so these touch fibres are now transmitting pain. There's also a syndrome in which the sympathetic nervous system becomes involved as well.

So any sympathetic nervous system activity augments the pain transmission. That's known as sympathetically maintained pain, whereby no suscept or activity increases sympathetic nervous system discharge and the no susceptors then acquire a noradrenaline sensitivity. There's a condition in people called complex regional pain syndrome where there is pain, but you also see autonomic effects in that painful area.

And that's an example where there's adrenergic receptors are coupled to the no receptors. Not very well defined in our veterinary patients, but potentially areas where you see sympathetically maintained pain in people is in pancreatitis cases and gallbladder pain, and we certainly see incredibly painful dogs and cats with pancreatitis and incredibly painful dogs certainly with gallbladder pain if we have to do a cardio cystectomy. So maybe there's some thought here we should be thinking, OK, these patients with this disease, do they have a sympathetically maintained pain?

Do we need to look at something to mediate the sympathetic side of things? So is there a rationale here for using something like a meatomidine or a dexedatomidine CRI for their analgesia rather than filling them up with with opioids? Because certainly for pancreatitis, anything abdominal, if we use high doses of opioids, we're going to see an increase in side effects associated with that, such as regurgitation, which and decrease in gut mortality, which you don't really want to see in either of these conditions.

So a great example of maybe where we need to think about widening out of our conventional analgesics and thinking in a real multimodal sense about these cases. So if we summarise that, look at mechanistic chronic pain etiologies, you can see that there are quite a diverse number of mechanisms, and we've thought about that in the context of some veterinary examples, so osteoarthritis, syringomyelia, some neuropathic conditions. There are a lots of other pain conditions and so.

I think what I'd encourage you to do now is any pain condition you think about, just think about where those mechanisms may be at play in that individual patient because that will help guide you towards the most appropriate solution, whether that's a pharmacological solution or whether we need to bring in some of those other factors that we talked about previously, the psychological, the physiological, and the social factors as well. Maybe to say solutions are sparse is a little bit sceptical because actually I think we've talked about quite a few, I've given quite a few examples of where we can intervene with a whole variety of agents that we do have at our disposal. And lastly, I'd say let's treat pain early and let's always think about a multi-modal approach.

Are you done, is that you done Matt? That's it, yeah, thank you very much. Fantastic, thank you very much for that.

Once again, there always some very, very useful tips and hints er for people to be able to take away into practise, and that's what these webinars are about really, is being able to draw on. Expertise like math, to help give you some, pointers and some real examples of how you can help, develop your, your skills and your knowledge base within their practise. So thank you very much.

As I mentioned, sorry, that was my cat that's just, popped up on the sofa and, is giving me a mouthful. It must be tea time for them. But, as I said, I'm the, head of sales for webinar vet, so please don't leave it to me to ask Matt some questions, because I haven't got a background in veterinary medicine there, but I'm sure you must have some questions, so please do, pop any questions as Matt has left a bit of time for us to ask any.

Just a reminder. At the end of this webinar, please do complete the, short feedback survey, as that is really useful for us, in terms of planning ahead for the future year. I believe it or not, we are looking at 2019 now already and that what that programme involves.

Right, I am glad to see I have got a question for you, Matt, and it's from Max. Hi Max. It says when I diagnose a dog or cat with OA, I always start with an NSAID.hould I be more multimodal from the start?

I, I don't think we honestly know the answer to that question yet. I think you're absolutely right to start with a non-steroidal every time. The important thing here is to give the non-steroidal long enough before you decide you need to add something else in, and typically we understand it probably takes about 4 weeks to wind down some of those inflammatory mechanisms that are going on there.

So, I would, when you start off on a non-steroidal, what I would do, I would start them on on non-steroidal. I would say to the owner, let's decide if this is going to be enough, and we are going to decide in 3 to 4 weeks' time, and that's when you schedule your revisit to bring the owners back. At that point, I would, I use a pain score, something like the cane and brief pain inventory or the load score at the first visit and then that second visit, and you're going to use that to work out whether you need to add in an adjunct at that stage.

And based on the current literature and experience, I would be adding in something like a mantidine or memantine at that stage, so that would be my approach. Fantastic. Thank you very much for that.

Has anyone else got any questions? Hopefully that is answered your question, Max. If anyone's got any observations about what Matt's gone, what Matt's gone through today, the approach you take and how that's gonna affect it, it would be great to hear from you.

As Matt said at the top of this, he has done a number of webinars on anaesthesia and analgesia, towards the end of last year and the beginning of this year. As well, so, please do, away from this webinar, have a look on our website. You can go to speakers, search for Matt, and, all the webinars that Matt has, delivered for us over the last couple of years will appear there so you can work through them and watch them as well.

So that is something for you to keep an eye out for. OK, we've got a couple more. Got, Max's just come out and said thanks.

I forgot about Amaadin. Yeah, I'm, I'm Antonine, sorry, my eyes going a bit wonky. And then someone else a superb webinar, fascinating topic and a very important one.

From personal experience, the more chronic the pain, the greater the need for multimodal, and I'm sure you'll agree with that, Matt. Yeah. Fantastic.

So I don't think we have got any more questions. So, all it leaves me to do is to thank Peter, who has been on, supporting from a technical side. To say thank you to, Matt, of course, for, tonight's presentation and also, to yourselves for listening.

Oh, just one question has just crept in just at the end there. Right, it's from Alicia. It said, please could you give us a bit more information on using amatidine?

Can it be used long term? Are there any side effects? Yes, you can definitely use Amanine long term.

I'm just trying to think where I've got some information. I haven't, I will put some information on Amanti on zeroo Pain philosophy.com.

That reference at the bottom there, I will write a blog on Amantadine for you guys to get some information on. But just briefly, you can use it in dogs and cats. It's a capsule and an oral solution, 3 to 5 mg per kg.

Start once daily. You can increase to twice daily if you don't see a response. You probably want to give it 2 to 3 weeks before documenting whether you've got a response, but I find the vast majority of older arthritic dogs respond very well to it.

Side effects would be, I've seen watery diarrhoea in one case in that though we stopped that, supportive therapy and then reintroduce the amantadine. I'm just trying to think. I haven't seen many other side effects with amantadine.

Yes, you can use it long term. Obviously it's off licence, so the same precautions apply with any long term, off-license drugs we can talk to the owner about it, warn them the side effects. In these older arthritic cases, I would take a blood sample before you start any chronic medication anyway, just looking at, I'm more concerned about biochemistry really, liver and kidney function, just so you know where you're starting from, and then you could just repeat that six months later.

And in a lot of those cases, I'm just doing a biochemistry profile once a year, just for peace of mind really. There's no, we, we don't have the evidence yet. How frequently we should be monitoring our chronic pain patients.

Fantastic. And so you said you very kindly said you'll do a blog on it. And what was that website?

Was it zeroo Pain? Zero Pain philosophy.com, it's just on the bottom of those reference that reference list there.

Oh sorry, I've got a yeah my my Q&A box is there blocking it there I can see it, yeah, so as it's that says in that bottom blue box, zeropahilosophy.com. So, no, that'd be great.

please do refer back to there as well. So, thank you for that, Matt. That'd be really appreciative, and, I know Luci said thanks a million as well.

So thank you very much for that. So once again, thank you very much for all for joining us. Please do tune in again at 8:30 next Thursday for another fantastic webinar, and, wish you all the best for the weekend.

Take care. Good night.