Hey.
I thought I would share a discussion from our members clinical discussion forum where were were discussing this exact topic:
Question:
Paracetamol in liver disease
We had a bit of a debate today regarding use of paracetamol in a dog with a confirmed liver neoplasm – if I had to guess from gross appearance I would say it appears aggressive and malignant. Liver parameters (ALT/ALKP) markedly raised.
Is paracetamol safe to use? I feel I have always thought ‘paracetamol is contraindicated in hepatic disease’. However, my colleagues suggested otherwise. So I feel a little confused!
Response:
Hi Laura,
That’s a great question, and I completely understand your hesitation. The traditional teaching has been that paracetamol is contraindicated in liver disease, but more recent evidence, particularly from human medicine, suggests that the reality is more nuanced.
In human patients with chronic liver disease, paracetamol is actually considered the first-line analgesic due to its relatively safer profile compared to NSAIDs and opioids. Prospective studies have shown that even in cirrhosis, therapeutic doses up to four grams per day for thirteen days were well tolerated. The primary concern with hepatotoxicity comes from overdose or in patients with additional risk factors such as alcoholism, fasting, malnutrition or febrile illness, all of which can contribute to glutathione depletion and increase the risk of NAPQI toxicity. Interestingly, studies indicate that the metabolism of paracetamol via glucuronidation and sulfation remains largely intact even in moderate to severe liver disease, with only a slight prolongation of half-life. Importantly, there has been no strong evidence that chronic liver disease itself significantly increases NAPQI production in the absence of other compounding factors.
That being said, the situation in this dog is different from stable chronic liver disease. Here, we are dealing with a confirmed liver neoplasm that, from gross appearance, seems aggressive and malignant, alongside significantly elevated ALT and ALKP. While we do not have a perfect veterinary parallel to human studies on paracetamol in liver disease, the presence of a tumor introduces additional uncertainties. Liver neoplasms, particularly aggressive ones, can disrupt normal hepatic metabolism in unpredictable ways, potentially impairing glucuronidation and glutathione-dependent detoxification of NAPQI. This makes the risk of hepatotoxicity harder to assess.
It is also worth considering that idiosyncratic drug reactions can occur with many medications, including those we otherwise consider safe, and paracetamol is no exception. Most drugs undergo some degree of hepatic and renal metabolism, and while the impact on these organs is usually predictable, unexpected adverse effects do happen. In a compromised liver, even drugs that are typically well tolerated can have altered pharmacokinetics and pharmacodynamics, potentially leading to increased toxicity. This is particularly relevant when hepatic metabolic pathways are already under strain due to disease, inflammation or neoplastic infiltration.
In a dog with stable liver disease and intact synthetic function, I might consider a cautious, low-dose approach with monitoring. However, in this case, given the unknowns surrounding liver function and the already elevated liver enzymes, I would be inclined to avoid paracetamol altogether if possible. There are safer alternatives for analgesia, including gabapentin, amantadine and opioids such as buprenorphine or fentanyl. If paracetamol were absolutely necessary, I would opt for a significantly reduced dose of ten milligrams per kilogram or less with close monitoring of liver function, including synthetic markers like albumin, bile acids and coagulation parameters.
So, while your instincts about paracetamol being contraindicated in hepatic disease are generally correct, the discussion is evolving and there are situations where it can be used safely. However, in this particular case, with a potentially compromised hepatic metabolism due to neoplasia, I would err on the side of caution and look for alternative analgesic options. Given the unpredictability of drug metabolism in compromised livers and the potential for idiosyncratic reactions, a conservative approach seems safest.
Let me know your thoughts. I will ask our anaesthetist, Felipe, for his comments too.
Best,
Scott 🙂
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
