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Paracetamol: it’s all about the dose

Updated: Sep 1, 2023

Paracetamol is one of the most under-used drugs in veterinary medicine. I’m talking here specifically about analgesia for dogs in the acute setting.


But there’s no evidence, right? Wrong! We now have a good amount of evidence that provides us clear direction regarding dose. I’ve explored this evidence in a recent webinar entitled ‘Paracetamol in dogs: the evidence in black & white’.

This pain update is a quick read – for a comprehensive understanding please watch our webinar.

Paracetamol’s precise mechanism of action is traditionally reported as unknown and several studies report varying potential actions. Recent work demonstrates that the anti-pyretic (central cyclo-oxygenase inhibition) and analgesic mechanisms are reported to be separate (Nilsson et al 2021), with this well-established research group demonstrating the significance of TRPV1-mediated anti-nociception.

When discussing paracetamol, the dose clearly differs between oral and IV use – which from basic pharmacokinetics, makes sense.

Paracetamol 15 mg/kg IV has been compared to meloxicam 0.2 mg/kg IV or carprofen 4 mg/kg IV in dogs undergoing ovariohysterectomy. In this study the outcome measures were pain scores and the use of rescue analgesics. These investigators showed that paracetamol at this dose was as effective as meloxicam or carprofen for controlling pain following this surgical procedure. The dogs were studied for 48 hrs with paracetamol administered every 8 hours during the study. No adverse events were noted in this study. Although a commonly used dose IV is 10 mg/kg, we don’t have evidence to support that dose so perhaps 15 mg/kg should become the new normal?

Original work examining the anti-inflammatory effect of paracetamol showed that at approx. 25 mg/kg TID per os paracetamol was analgesic in dogs, but lacked significant anti-inflammatory effect. When 10 mg/kg PO was trialled in the same study design an analgesic effect was not demonstrated. These studies were from 1988 and 1991 so it is not clear where the commonly used 10mg/kg PO came from – it’s probably not effective in the majority of dogs. These studies were rudimentary in design and lacked a sample size calculation.

Many years later a study examining paracetamol in combination with hydrocodone showed that a dose of 13-18 mg/kg did not provide acceptable analgesia following stifle surgery.

A recent study compared oral paracetamol/codeine (Pardale-V – the licensed UK product) with meloxicam given orally prior to surgery. Paracetamol was dosed at 33mg/kg PO TID (the licensed dose) and meloxicam at 0.2mg/kg PO initially followed by 0.1 mg/kg. Both drugs were given for 3 days. Non-inferiority was demonstrated between Pardale V and meloxicam. This provides us with useful evidence regarding oral dosing and gives us options for those dogs that cannot tolerate an NSAID but are undergoing surgery. It should be noted that these dogs received methadone as premedication and buprenorphine every 8 hours post op.


In a paper entitled ‘Intravenous Acetaminophen Does Not Provide Adequate Postoperative Analgesia in Dogs Following Ovariohysterectomy’, Leung and others (2021) investigated paracetamol 20 mg/kg IV administered following surgery and prior to recovery, compared to saline placebo. Pethidine 7 mg/kg was included in premedication in all dogs. Pain was scored using the validated SFGCPS at 10, 20, 60, 120 and 180 mins after extubation and the recommended intervention level was applied. Rescue analgesia was provided using methadone and meloxicam.

These authors also determined plasma concentrations of paracetamol using liquid chromatography.

A sample size calculation of 14 dogs per group was based on administration of rescue analgesia to 5% of dogs in the paracetamol group and 50% in the control group.

Only 7 dogs per group completed the study. The study was terminated early due to high requirement for rescue analgesia in both groups plus the fact that pethidine became unavailable during the study. In both groups, 3/7 dogs required rescue after the 20-minute pain score and 4/7 dogs in both groups at 60 minutes post-surgery. It is interesting to note the differences in timing of pain scoring between this study and the Pacheco work in the early recovery period where the latter started pain scoring at the two-hour post recovery point.

It is likely that this work resulted in a type II error and further subjects are required to draw conclusions.

For considerations when using paracetamol for chronic pain click here for our pain update.


So it is clear that when using paracetamol we need to think dose and route of administration. I hope you enjoy the webinar!


This post was written by Matt Gurney. Matt & Carl established Zero Pain Philosophy to provide educational resources to veterinary professionals enabling optimal management of pain. Matt Gurney is an RCVS & European Specialist in Veterinary Anaesthesia & Analgesia and works at Anderson Moores Veterinary Specialists. Matt is ast PPresident of the European College of Veterinary Anaesthesia & Analgesia. Carl Bradbrook is an RCVS & European Specialist in Veterinary Anaesthesia & Analgesia and is Past President of the Association of Veterinary Anaesthetists. Carl works at Anderson Moores Veterinary Specialists.

References

González-Blanco P, Canfrán S, Mota R, Gómez de Segura IA, Aguado D. Effects of a single paracetamol injection on the sevoflurane minimum alveolar concentration in dogs. Can J Vet Res. 2020 Jan;84(1):37-43.


Hernández-Avalos, I., Valverde, A., Ibancovichi-Camarillo, J. A., Sánchez-Aparicio, P., Recillas-Morales, S., Osorio-Avalos, J., Rodríguez-Velázquez, D., & Miranda-Cortés, A. E. (2020). Clinical evaluation of postoperative analgesia, cardiorespiratory parameters and changes in liver and renal function tests of paracetamol compared to meloxicam and carprofen in dogs undergoing ovariohysterectomy. PloS one, 15(2), e0223697. https://doi.org/10.1371/journal.pone.0223697


Högestätt, E.D., Jonsson, B.A., Ermund, A., Andersson, D.A., Bjork, H., Alexander, J.P., Cravatt, B.F., Basbaum, A.I., Zygmunt, P.M. (2005). Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugationin the nervous system. J Biol Chem 280, 31405–31412


Leung J, Beths T, Carter JE, Munn R, Whittem T, Bauquier SH. Intravenous Acetaminophen Does Not Provide Adequate Postoperative Analgesia in Dogs Following Ovariohysterectomy. Animals (Basel). 2021 Dec 20;11(12):3609. doi: 10.3390/ani11123609.


Mburu DN, Mbugua SW, Skoglund LA, Lökken P. Effects of paracetamol and acetylsalicylic acid on the post-operative course after experimental orthopaedic surgery in dogs. J Vet Pharmacol Ther. 1988 Jun;11(2):163-70. doi: 10.1111/j.1365-2885.1988.tb00137.x.


Mburu DN. Evaluation of the anti-inflammatory effects of a low dose of acetaminophen following surgery in dogs. J Vet Pharmacol Ther. 1991 Mar;14(1):109-11. doi: 10.1111/j.1365-2885.1991.tb00811.x.


Merrill GF, Merrill JH, Golfetti R, Jaques KM, Hadzimichalis NS, Baliga SS, Rork TH. Antiarrhythmic properties of acetaminophen in the dog. Exp Biol Med (Maywood). 2007 Oct;232(9):1245-52. doi: 10.3181/0701-RM-19.


Nilsson JL, Mallet C, Shionoya K, Blomgren A, Sundin AP, Grundemar L, Boudieu L, Blomqvist A, Eschalier A, Nilsson UJ, Zygmunt PM. Paracetamol analogues conjugated by FAAH induce TRPV1-mediated antinociception without causing acute liver toxicity. Eur J Med Chem. 2021 Mar 5;213:113042. doi: 10.1016/j.ejmech.2020.113042. Epub 2020 Nov 21.


Pacheco M, Knowles TG, Hunt J, Slingsby LS, Taylor PM, Murrell JC. Comparing paracetamol/codeine and meloxicam for postoperative analgesia in dogs: a non-inferiority trial. Vet Rec. 2020 Oct 17;187(8):e61. doi: 10.1136/vr.105487.


Pickering G, Creveaux I, Macian N, Pereira B. Paracetamol and Pain Modulation by TRPV1, UGT2B15, SULT1A1 Genotypes: A Randomized Clinical Trial in Healthy Volunteers. Pain Med. 2020 Apr 1;21(4):661-669. doi: 10.1093/pm/pnz037.


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6 Comments


Kamil Ślachciak
Kamil Ślachciak
Apr 18, 2023

Hello! Please could you reference the mentioned studies looking into the doses and their effect? I tried looking them up, but no luck.

Best wishes,

Kamil

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Kamil Ślachciak
Kamil Ślachciak
Apr 19, 2023
Replying to

Many thanks!

Kam

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Tanya Manser
Tanya Manser
Aug 12, 2021

So, for acute musculoskeletal pain/whiplash in a 10kg whippet, 250mg PO TID would be preferable to 100mg BID?

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Tanya Manser
Tanya Manser
Aug 13, 2021
Replying to

Hi Matt, Thank you for your reply. My vet said paracetamol, without mention of NSAIDs. Unfortunately, the suggested 10mg/kg appeared to offer insufficient pain relief yesterday.

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