Felipe M.

Hi Scott (and delegate!)

What a fantastic question.

Well done to our delegate, the approach is already very sensible indeed. However I cannot refrain from taking the chance to chip in to a couple of concepts.

When wanting to avoid or decrease the dose of sedatives to avoid their side effects, using higher doses of opioids is a great option. I would go as high as 0.5mg/kg butorphanol/methadone, or start with a similar 0.3mg/kg dose and top up at any given time with 0.1mg/kg up to twice, to deepen the sedation.

I will many times introduce some acepromazine at low doses (5-10mcg/kg) 20 min before the opiod to have some background sedation and additive/drug sparing effects. Obviously we don’t want to go much higher as lowering the blood pressure too much with a long-lasting agent in a hypertensive patient with an up-regulated organ perfusion auto-regulation is not desirable either.

There is some value in having a very dilute low dose of medetomidine/dexmedetomidine (1-2mcg/kg in 5-10mL of saline) and administering over 5-10 minutes to get sedation with much less pronounced vasoconstriction. This is very much case and blood pressure values dependent, but in the cases where the animal is fit for them, the quality of the sedation is better than in any other combination. Introducing a benzodiazepine with this technique, to spare the dose given is a very good way forward too, more on that below!

Using alfaxalone (or propofol) at subanaesthetic doses to achieve a sedation can be very helpful in these scenarios, but caution must be exercised as anaesthesia can be induced inadvertently and airway compromise may happen (due to obstruction, hypoventilation or aspiration). I would say that personally I find these drugs, compared to alpha-2 agonists at equivalent sedation levels, cause more respiratory depression and loss of airway protective reflexes, which I am not a fan of. I always recommend to have means to intubate and ventilate at the ready next to any sedated animal, much more so if these drugs are used.

Introducing a benzodiazepine (especially after a low dose of alfaxalone/propofol, so as to avoid hyperexcitability) can be very helpful to deepen the sedation with less side effects than if we continued with the anaesthetic agent. I do this many times in cats (or even in cases where I used opioid and some alpha-2 agonist, to spare the alpha-2 agonist dose) and usually it works great. I have to say I personally do not do this in dogs as often, given they are more prone to hyperexcitability and even display of aggressive behaviour.

In some cases I do use more complex combinations to spare drug dosing and side effects. As an example, I may start with 5mcg/kg acepromazine 20 minutes before the rest, then give butorphanol, then a very dilute alpha-2 agonist, and when I do not want to go any higher with alpha-2 agonists, deepen with alfaxalone or midazolam (or even both) at lower doses.

Hope this helps! Please let me know if you would like me to elaborate further.

Felipe

Replying to Bethany Deadman 09/03/2025 - 16:34

Hi Bethany

Pregabalin is regarded as a bit more predictable in its effects in humans, requiring less titration to reach a reliable clinical effect. The pharmacodynamics are quite complex because it does not work only on calcium channels, but in several other receptors, which makes it appear more advantageous. This article supports the pharmacokinetics in dogs: 10.1111/j.1467-2995.2009.00486.x

In terms of NMDA antagonists, I do use them a lot in OA or any other type of sensitisation, including visceral. At the end of the day, what we are targeting is the open and working NMDA receptor in the dorsal horn of the spinal cord, which is causing the second order neuron to depolarise more easily. I do introduce them quite early in OA, even if in pulse therapy, if NSAIDs on their own do not yield all the effects I want. It’s the same principle as giving SQ ketamine every now and then, since ketamine, amantadine and memantine work in similar ways. Amantadine did have a restriction to its use in EU due to more astringent antiviral prescription guidelines, but we did not seem to get it in UK. However, I tend to prescribe even more frequently memantine, which is another molecule that works in the same NMDA receptor, but to my knowledge not regarded as an antiviral and still fine to be dispensed in EU countries under their equivalent to the cascade.

Felipe

Replying to Bethany Deadman 02/03/2025 - 17:17

Hi Bethany (and Scott)

I agree, there is a big challenge in many cases when transitioning from an in-patient to out-patient pain management. Without any doubt.

I tend to rely a lot on gabapentin too. Although primarily used for neuropathic pain, there are reports of its use even in acute pain cases (the one that comes to mind, in a cat) with a very good result. I many times use gabapentin in a multimodal approach as soon as the animal allows tablets, to de-escalate the parenteral medication. Pregabalin is a drug I use nowadays even more than gabapentin, with superior analgesia effects in dogs due to higher bioavailability. It can cause also more sedation at times, so evaluating the effect in each patient will direct me towards changing to gabapentin in some cases.

But obviously, gabapentin/pregabalin is not the cure for everything! and many animals need stronger analgesia.

I agree with Scott, if I am against paracetamol, I will stay away from NSAIDs as well for the reasons he has nicely stated.

Another one to use, especially if there is visceral sensitisation (or any other type of sensitisation), or somatic pain, is amantadine/memantine, which are also a good option within the multimodal approach.

Although always keeping a healthy amount of skepticism due to its very large interindividual variability in effects, I do consider trialing oral tramadol as it will work in some animals. If I need more reliable analgesia than this, I will then move on to oral-transmucosal buprenorphine. This has been proven to work both in dogs and cats.

If things are beyond this, I would re-consider keeping the animal as in-patient. If the animal must be discharged but is beyond the above, a fentanyl patch (ensuring the owners are also good candidates for this) can yield very good results too, with only visits needed every 3 days.

Hope this helps!

Felipe

Hi Bethany

First of all, it seems you did already a fantastic job, well done!

Hypoalbuminaemia can make things certainly tricky. In first place it will make a higher free fraction of the drug to be present due to lower binding capacity (albumin for neutral and acid drugs, alpha 1 glycoprotein for bases, such as local anaesthetics). Additionally the lower COP and glycocalyx disturbance will cause adverse fluid shifts and make patients more likely to become hypotensive. Lastly, acid-base status can be affected by hypoproteinaemia (reflected in the Atot in Stewart’s approach).

So, with all this in hand it seems it was a great idea to infuse some albumin beforehand, even if the net effect wasn’t so impressive in the end. At that low level of serum proteins I would have done the same, more for the COP/glycocalyx than for the altered pharmacokinetics, which I can otherwise adjust the dosing for.

In terms of the dosing, I find difficult to set standardised values for dosing indexed for the protein levels. This is so because the drugs commonly used in anaesthesia have a quite wide therapeutic window, and thus many times (but certainly not always) we won’t see dramatically different effects from administering 50% to even 100% more free fraction. In the case of induction agents, they are dosed to effect so we more or less bypass the problem. Even so, I tend to estimate the percentage decrease of albumin from the normal serum levels, and decrease my doses by roughly the same. In your case, given albumin was around half the normal levels, I would have gone with 0.1mg/kg of both butorphanol and midazolam. However, you can see things went very smoothly for you, so clearly what I wrote above applies in many cases.

Administering FFP as a fluid was also a great choice to not dilute COP further and promote IV compartment retention of fluids. Certainly better than synthetic colloids!!! (dare I say their name…)

Noradrenaline would probably have been my plan B too, if the heart rate had been on the higher side (more likely than not), there was no response to fluids and there was no other contraindications.

Very complex cases with several potential complications!

Hope this is of help, but let me know if you need further information.

Felipe

Hi Bethany

Great question!

Unfortunately all the information we have so far from SQ ketamine is anecdotal. I do agree it does seem to work in many animals, yielding an improvement in comfort levels sometimes for weeks.
Pharmacokinetically the most probable way things work is that ketamine is absorbed, metabolised and excreted within a couple of hours at a maximum, however parmacodynamically, having exerted its action on the NMDA receptors does help in “resetting” to some extent the ascending pain pathways at the time, and helps other drugs be more effective. This causes a clinical effect that can be seen for weeks sometimes, but I would say caused by a short term pharmacological effect. I typically use 0.5-1mg/kg SQ.

Unfortunately a SQ dose of ketamine cannot substitute an infusion. Using a ketamine infusion will always yield more profound effects, and actually having the patients on the infusion for 24-48h will have more chances at resetting the biochemical wind up than only doing so for 4-6h. So depending on the severity of the condition I will choose from a SQ injection as an add-on, an infusion for a couple of hours, or a protracted therapy for 1-2 days.

Hope this helps!

Felipe

Hi again Bethany

Please do send as many questions as you like, very happy to help! Medicine patients are certainly amongst the more complex needing careful balancing of the anaesthetic.
There are certainly many ways to approach anaesthesia in these animals, but I tend to focus on:
– Short acting and where possible antagonisable drugs, accounting for potentially impaired metabolism.
– Glycaemia control, as you well mentioned.
– Maintaining temperature, to not depress the metabolism of the liver, in animals more prone to hypothermia for several reasons (age, size, condition, lower liver metabolic activity).
– Maintenance of vasomotor tone, given they have higher circulating nitric oxide and are prone to hypotension, many times not very responsive to treatment.
– Accounting for a delayed drug metabolism when repeating dosing of, for example, analgesics.
– Dose adjustment if albumin is low.

So with all this in hand, I tend to use:
– Alpha-2 agonists (if over 12 weeks of age): historically dexmedetomidine is favoured as dosing is half of that of medetomidine. Theoretically, we are only loading the liver with half the metabolic burden. I do follow this thought for infusions where accumulation can happen, but for a single pre-anaesthetic sedation dose I do think pragmatically there is no clinical difference in most of the animals.
– Methadone: even if there is no pain involved in the procedure, as I can antagonise it with naloxone if necessary, to speed up the recovery. Using butorphanol is not wrong, however we lose the ability to antagonise it should we see narcosis in recovery.
– Propofol or alfaxalone: both alfaxalone and propofol are metabolised in the liver, with a small extrahepatic metabolic fraction in the lungs and kidneys. The cessation of the clinical effect happens in both cases by re-distribution rather than metabolism, so both of them are adequate.

When it gets to surgical correction, the use of PIVA for MAC sparing reasons with alpha-2 agonists or opioids is most ofter needed to help avoid hypotension, although vasoactive drugs are often needed as well.

It seems you did a great job already, and there is certainly value in following a regime we are most comfortable with!

Hope this is of help.

Felipe

Hi Laura and Scott

What an amazing and interesting topic, which is discussed a lot everywhere I find.

I honestly doubt there is any way I can give any more scientific background information than Scott has already done. What a great summary, thanks for that Scott.

I completely agree with Scott. With all that scientific background in hand, and looking at what our human anaesthetist counterparts do, paracetamol does seem to be accepted as quite safe in many scenarios, and have a fairly wide therapeutic window. This is even reflected by its wide dosing regimes that can be read on the BNF NICE guidelines. This seems to be consistent in dogs where we know acute single dose toxic levels in dogs were reached around 75 to 100mg/kg (not that I would ever recommend getting even remotely close). Cats are obviously a totally different case.

These cases where there is uncertainty about the competency of the metabolic routes and the handling of NAPQUI are certainly tricky and I would therefore stay away from it. Unfortunately we just do not have the large population data to understand better the suitability in these disease processes. All the decisions we make for our patients are risk-benefit assessments, and I would find quite hard to justify any considerable risk for the benefit achieved through paracetamol therapy, if we have other options, many of which yield superior analgesia.
I would also argue that given the lack of data, the inherent potential hepatotoxicity, and the fact that the only paracetamol preparation licensed in dogs has a literal contraindication in liver disease, should we be so unlucky to find the patient that was not fit for paracetamol, we would have a very hard time legally justifying our choice.
In general, I have to admit that although I do love paracetamol for most canine patients, I am often quite defensive in its use in hepatic disease cases. Even if I know in many cases the patient would almost certainly be fine with paracetamol, I steer away from using it if I can find another alternative. If there is no other alternative, an honest discussion with the owner with paper trail of our reasoning and written consent seems sensible.
In terms of considering dosing adjustment for these animals, and expanding on what Scott rightly said, I personally end up finding that if I am worried about accumulation (which I guess could saturate metabolic routes/deplete our beloved glutathione in impaired animals) and I am not able to predict pharmacokinetics, it’s another reason for me to just not use it. Lowering the dose obviously makes sense if accumulation is likely, but if plasma levels are too low we risk not yielding a clinical effect. So if I still were to go ahead with this, I would go with the lowest of the dosing that we know have a clinical effect but consider decreasing the doses per day to allow for a longer half life (for example to q12h or even q24h), rather than preserving a TID regime with lower dose which might not yield high enough plasma concentration, or rely on a very difficult to predict (and potentially dangerous) accumulation to do so. When pharmacokinetics start getting messy I tend to throw my toys out of the pram, but this is just my personal opinion, not necessarily the best one! In any case, monitoring, as Scott said, would be very important.

Hope this helps!

Felipe