Assessing the use of IV paracetamol as an alternative to NSAIDs for post-operative analgesia

Imagine this clinical scenario: a geriatric dog is presented for ovariohysterectomy after being diagnosed with stage two renal disease. You want to provide pre- and post-operative analgesia to the patient and would typically use non-steroidal anti-inflammatories (NSAIDs) as they are commonly used to produce post-operative analgesia in healthy dogs. However, the presence of renal disease in the patient may increase the risk of kidney ischaemia and damage during periods of hypotension when using NSAIDs. You therefore identify intravenous (IV) paracetamol as a potential alternative to NSAIDs but decide to consult the evidence to deduce whether IV paracetamol would be a good alternative to NSAIDs to provide post-operative analgesia.

The evidence

Three randomised controlled blinded studies were reviewed. Two papers – Hernández-Avalos et al. (2020) and Leung et al. (2021) – directly addressed the research question, while the third study by González-Blanco et al. (2020) evaluated the effect of IV paracetamol on sevoflurane minimum alveolar concentration (MAC).

Hernández-Avalos et al. (2020) studied 30 client-owned dogs undergoing elective ovariohysterectomy. Ten of the patients were given IV paracetamol, while the remaining 20 were given NSAIDs, with 10 given carprofen and 10 given meloxicam. IV paracetamol was administered every 8 hours and NSAIDs every 24 hours. The evaluator was blinded. The outcomes studied were post-operative analgesia, cardiorespiratory parameters, and liver and renal function.

Leung et al. (2021) studied 14 client-owned dogs undergoing elective ovariohysterectomy. Seven dogs were given IV paracetamol and the other seven were given the equivalent volume of saline. The placebo and IV paracetamol were administered by an individual not involved in pain assessment to maintain blinding. The outcomes studied were post-operative analgesia in addition to measuring paracetamol plasma concentrations.

González-Blanco et al. (2020) studied seven healthy adult laboratory Beagle dogs. The dogs were anaesthetised on two separate occasions and treated with a single IV injection of either paracetamol or the equivalent volume of saline. After a 20-minute equilibrium period, the MAC of the gaseous agent sevoflurane was assessed in response to a mechanical noxious stimulus.

Limitations of the evidence

The overall quality of evidence was weak, owing to a variety of limitations across the three papers studied. All three papers had small sample sizes: seven patients (González-Blanco et al., 2020), 14 patients (Leung et al., 2021) and 30 patients (Hernández-Avalos et al., 2020). There were issues with sample size calculation; Hernández-Avalos et al. did not provide an explanation for their sample size calculation. Meanwhile, Leung et al. provided a sample size calculation identifying a minimum size of 14 dogs per test group but only included seven dogs per group. This is because the study was terminated early due to ethical concerns. In both of these papers, type II statistical errors cannot be ruled out.

Further weaknesses in Hernández-Avalos et al. (2020) were the use of a pain scoring system unvalidated for canine use, differing scoring systems used for different patients, plasma paracetamol concentrations not being measured and lack of a negative control group.

In both the Hernández-Avalos et al. (2020) and Leung et al. (2021) studies, different additional opioid protocols were used, which added a variable to the studies, making comparison difficult. In these studies, the timing of the IV paracetamol administration also differed: Hernández-Avalos et al. used paracetamol perioperatively, while Leung et al. used it post-operatively.

Both González-Blanco et al. (2020) and Leung et al. (2021) measured low plasma paracetamol concentrations, which may have been the reason for any lack of effectiveness of the drug.

González-Blanco et al. (2020) had the following further weaknesses: limited applicability to the research question and lack of information on how the study was blinded.

Summary of findings

The overall quality of evidence is weak due to the limited number of studies available and the limitations of those that do exist

The overall quality of evidence is weak due to the limited number of studies available and the limitations of those that do exist. Additionally, two of the studies appear to directly contradict one another; Hernández-Avalos et al. (2020) found a reduction in pain in all groups with no differences in analgesia between NSAIDs and IV paracetamol, while Leung et al. (2021) found no analgesic effects from IV paracetamol and terminated their study prematurely because a high number of patients required rescue analgesia. Both studies directly addressed the research question and had a robust study design; however, their methods and sample sizes were not sufficient.

The results of González-Blanco et al. (2020) did not demonstrate a clinically relevant sevoflurane MAC reduction following the administration of IV paracetamol in dogs.

Conclusion

Further studies are required to assess its efficacy, its duration of action and the appropriate doses necessary to reach therapeutic plasma levels

The papers studied provide limited and weak evidence to suggest that IV paracetamol provides peri- and post-operative analgesia in dogs. However, further studies are required to assess its efficacy, its duration of action and the appropriate doses necessary to reach therapeutic plasma levels. Any future studies should also study larger sample sizes to improve the strength and reliability of evidence.

Disclaimer

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