KNOWLEDGE SUMMARY

Keywords: CANINE; DOGS; INTRAVENOUS PARACETAMOL; PERIOPERATIVE ANALGESIA; POSTOPERATIVE ANALGESIA

The peri / postoperative analgesic effect of intravenous paracetamol in dogs

Laura Mckay, RVN Ncert A&CC / ECC^1*

¹ The Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush Campus, Midlothian, EH25 9RG
* Corresponding author email: lauramckay2805@gmail.com

Vol 9, Issue 2 (2024)
Submitted 01 Aug 2023; published: 04 Apr 2024; next review: 14 Dec 2025
DOI: https://doi.org/10.18849/ve.v9i2.683

PICO question

In healthy dogs undergoing a surgical procedure, is there improved pain control in dogs receiving intravenous paracetamol in the peri / postoperative period compared to dogs not receiving intravenous paracetamol?

Clinical bottom line

Category of research

Treatment.

Number and type of study designs reviewed

Three randomised, controlled, and blinded studies. Two studies directly address the PICO question whereby postoperative pain assessment was clinically evaluated following intravenous (IV) paracetamol. The third study addressed the question to a lesser extent, whereby the impact on the sevoflurane minimum alveolar concentration (MAC) reduction in response to noxious stimuli was assessed following the administration of IV paracetamol.

Strength of evidence

Weak.

Outcomes reported

The findings of the first two studies presented appear to directly contradict each other. The first study demonstrated a reduction in pain in all groups and found no differences in analgesia between IV paracetamol and other non-steroidal anti-inflammatories drugs (NSAIDs), while the second study reported no analgesia effects from IV paracetamol and was terminated prematurely because a high number of dogs required rescue analgesia. The first study reported sufficient analgesic effects of IV paracetamol and the second study reported no analgesia effects of IV paracetamol. Both were blinded, randomised, controlled studies and directly addressed the PICO question in relation to the peri / postoperative analgesic effects of IV paracetamol. However, their methods and sample sizes were very different. The third study did not demonstrate a clinically relevant sevoflurane MAC reduction after IV paracetamol in dogs.

Conclusion

At present, there is limited and weak evidence to suggest that IV paracetamol provides peri / postoperative analgesia in dogs. However, further studies are required to better assess its efficacy, its duration of action, and the appropriate doses that are necessary to reach therapeutic plasma levels. The reduced incidence of side effects at the currently recommended doses could support its peri / postoperative use, where NSAIDs use is contraindicated.

How to apply this evidence in practice

The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources.

Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

Clinical scenario

A geriatric dog diagnosed with stage two renal disease is presented for ovariohysterectomy. While non-steroidal anti-inflammatories drugs (NSAIDs) are commonly used to produce postoperative analgesia in healthy dogs, their administration in this specific case might be contraindicated because of the renal disease. Inhibiting the cyclooxygenase enzymes and the production of prostaglandins, NSAIDs increase the risk of kidney ischaemia and damage during periods of hypotension (KuKanich et al. 2012). Therefore, would intravenous (IV) paracetamol be a good alternative to NSAIDs to provide postoperative analgesia with low incidences of adverse side effects?

The evidence

The results of three randomised, controlled, and blinded studies are included. While two of those studies (Hernández–Avalos et al., 2020; and Leung et al., 2021) directly addressed the PICO question, the third study (González-Blanco et al., 2020) evaluated the effect of intravenous (IV) paracetamol on sevoflurane minimum alveolar concentration (MAC). The evidence is contradictory in some areas and, overall, is limited and weak.

Summary of the evidence

Hernández-Avalos et al. (2020)

 

Leung et al. (2021)

 

González-Blanco et al. (2020)

 

Appraisal, application and reflection

In the UK, a product containing paracetamol and codeine is licensed in dogs as an oral formulation (Pardale- VTM). In particular, 33 mg/kg of paracetamol and 0.75 mg/kg codeine repeated every 8 hours can be administered to dogs for up to 5 days. In dogs undergoing different types of surgeries, the postoperative analgesic effect of a paracetamol-codeine administered every 8 hours was not inferior to meloxicam (Pacheco et al., 2020). The aforementioned studies in the summary of evidence utilise a human formulation of intravenous paracetamol. There is no veterinary licensed equivalent.

According to the BSAVA Formulary (BSAVA, 2020), paracetamol should be administered at 10–20 mg/kg intravenously (IV). While a pharmacokinetic study was performed using this dose range in Beagle and Galgo español dogs, the variable therapeutic range observed between the two dog breeds made the authors conclude that further investigations were warranted to better understand the paracetamol pharmacokinetic properties in the context of anti-nociception in dogs (Serrano-Rodríguez et al., 2019).

Despite that the results of Hernández-Avalos et al. (2020) and Leung et al. (2021) appear to contradict each other, the methodology used makes a comparison between them difficult. Both of them are blinded, randomised, controlled studies, and they tried to address the PICO question in relation to the postoperative analgesic efficacy of paracetamol. In both studies, dogs undergoing ovariohysterectomies were used. Still, the intraoperative analgesic technique employed was different and could have affected the level of postoperative pain and, therefore, the effectiveness of paracetamol. While in Leung et al. (2021), preoperative pethidine was administered as an analgesic, a fentanyl constant rate infusion was used by Hernández-Avalos et al. (2020).

Pethidine is a synthetic opioid and has been shown to provide a dose-dependent effect in dogs, with 3.5 mg/kg intramuscularly (IM) providing 90 minutes of analgesia (Waterman & Kalthum, 1989). According to Lascelles et al. (1997), pethidine (5 mg/kg IM) is an effective but short-acting analgesic in dogs undergoing ovariohysterectomy. Vettorato & Bacco (2011) showed that pethidine (5 mg/kg IM) produced postoperative analgesia up to 4 hours in dogs undergoing ovariectomy or ovariohysterectomy.

The study from Hernández-Avalos et al. (2020), a perioperative fentanyl constant rate infusion (5 mg/kg/hr IV) was administered. Fentanyl is a potent, short-acting opioid and has been shown to provide adequate analgesia in dogs undergoing ovariohysterectomies at 10 mg/kg/hr IV (Gutierrez-Blanco et al., 2015). According to De Moura et al. (2022), fentanyl infusions at 5 mg/kg/hr IV provided adequate peri and postoperative analgesia in dogs undergoing surgical mastectomies. The quality of perioperative analgesia was considered ‘good’ in dogs receiving fentanyl at 4 mg/kg/hr IV while undergoing orthopaedic surgery, although rescue analgesia was required in 4/8 (50%) of cases (Bufalari et al., 2007).

The study by Leung et al. (2021) did not find a statistical difference between paracetamol (20 mg/kg IV) and saline. However, the study was terminated prematurely. Considering the results obtained (rescue analgesia was needed in 4/7 (57.1%) of dogs in the paracetamol group and 6/7 (85.7%) of dogs in group saline), at least 40 dogs per group would have been required to prove the superiority of paracetamol. Furthermore, paracetamol was administered postoperatively. It is unknown if its preoperative administration, at 20 mg/kg or higher doses, would have produced a better postoperative analgesic effect. However, it is probable that paracetamol alone is not a very effective analgesic in dogs undergoing ovariohysterectomy.

The pre-emptive administration of paracetamol, even at a lower dose (15 mg/kg IV), might be responsible for the better postoperative analgesia reported by Hernández-Avalos et al. (2020). This study concluded that the effect of paracetamol is equivalent to that of meloxicam and carprofen. However, plasma concentrations were not analysed. According to Leung et al. (2021), 40 minutes after the IV administration of paracetamol (20 mg/kg), its plasmatic concentration was < 10 µg/ml in all dogs. This is well below the plasma concentration that provides analgesia in humans (Gibb & Anderson, 2008; and Brett et al., 2012). Therefore, more research is warranted to better characterise the optimal dose and the analgesic activity of paracetamol in dogs. The two clinical studies used different methods to assess pain. The Hernández-Avalos et al. (2020) study used the Dynamic Interactive Visual Analogue Scale (DIVAS) and the University of Melbourne Pain Scale (UMPS), both of which are non-validated in the dog. In contrast, Leung et al. (2021) used the Short Form Glasgow Composite Pain Scale, which is a multi-item behavioural pain assessment tool developed and validated using a psychometric approach in the dog (Reid et al., 2007).

In Hernández-Avalos et al. (2020) study, one individual performed all the assessments, but it is impossible to rule out if one scale influenced the results of the second one. Therefore, both studies should be interpreted with caution.

The third study outlined in this summary (González-Blanco et al., 2020) is a well-designed study which also used a 15 mg/kg paracetamol dose similar to the Hernández-Avalos et al. (2020) study. A plasma sample was obtained 2 minutes after the administration of paracetamol and approximately 2 hours later. Similarly to Leung et al. (2021), the plasma concentrations of paracetamol falls below therapeutic levels 2 hours after its administration. The baseline minimum alveolar concentration (MAC) value of sevoflurane was determined 20 minutes post-induction of anaesthesia (MAC1), and a second MAC value (MAC2) was determined 2–2.5 hours after paracetamol or saline administration. While the MAC2 value of the paracetamol group was 15% lower than the control group, it was identical to MAC1. Instead, in the saline group, MAC2 was 15% higher than MAC1. Therefore, the difference found was not deemed clinically significant by the authors. The results of this study might be affected by the small sample size, by the use of propofol as an induction agent that could have affected MAC1 measurements, and the fact that the therapeutic plasmatic concentrations of paracetamol were potentially too low for the type of noxious stimulus applied to determine MAC2. Furthermore, this study is less relevant to the PICO question as it does not evaluate postoperative analgesia but an anti-nociceptive effect.

Despite many drugs having a MAC-sparing effect without inducing analgesia (i.e. acepromazine), analgesic drugs can have analgesic effects without producing a clinically relevant MAC-sparing effect (i.e. NSAIDs) (Reed & Doherty, 2018). According to Yamashita et al. (2008), a reduction of MAC was demonstrated by carprofen and meloxicam by 11% and 13%, respectively, similar to what was reported by González-Blanco et al. (2020).

All three reviewed studies reported no adverse side effects after a single IV paracetamol injection. In particular, Hernández-Avalos et al. (2020) did not report any change in cardiorespiratory, liver and renal parameters up to 48 hours postoperatively following 8 hourly continued IV paracetamol administered in healthy dogs. However, toxic side effects, including depression, weakness, recumbency and methaemoglobinaemia, were observed following the administration of a single dose of 150 mg/kg IV of paracetamol in dogs (St. Omer & Mohammad, 1984). While paracetamol (15–20 mg/kg IV) seems to be safe in healthy dogs, further research is required to fully evaluate its real analgesic effect, the dose at which it should be used, and the potential side effects caused by repetitive administration in both healthy and non-healthy dogs.

Methodology

Search strategy

 

Exclusion / inclusion criteria

 

Search outcome

 

ORCiD

Laura Mckay: https://orcid.org/0009-0004-7079-814X

Conflict of interest

The author declares no conflicts of interest.

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