KNOWLEDGE SUMMARY

Keywords: OVARIOHYSTERECTOMY; FELINE; BUPIVACAINE; LOCAL ANAESTHESIA; POSTOPERATIVE PAIN; PERIOPERATIVE ANALGESIA; NEUTERING; SPAY

In cats undergoing midline ovariohysterectomy, is the use of local anaesthesia with bupivacaine associated with a reduction in postoperative pain score?

Tara Freeman, Bsc (Hons) RVN^1*
Amelia Wisbey, Fdsc RVN¹
Kate Burroughs, Bsc (Hons) RVN¹
Samantha Gentle, Bsc (Hons) RVN¹
Connie Ellis, Fdsc RVN¹
Sarah Batt-Williams, MSc Vet Ed. FHEA Bsc (Hons) RVN¹

¹ The Royal Veterinary College, Hawkshead Lane, Hatfield, Hertfordshire, AL9 7TA, UK
* Corresponding author email: tfreeman18@rvc.ac.uk

Vol 8, Issue 1 (2023)
Submitted 29 Oct 2021; Published: 22 Feb 2023; next review: 09 Sep 2024
DOI: https://doi.org/10.18849/ve.v8i1.552

PICO question

In cats undergoing midline ovariohysterectomy, is the use of local anaesthesia with bupivacaine via intraperitoneal or subcutaneous injections, in comparison with the use of a control substance or other analgesic measure, associated with a reduction in postoperative pain score?

Clinical bottom line

Category of research

Treatment.

Number and type of study designs reviewed

Three studies were critically appraised in this Knowledge Summary. They included two prospective, blinded, randomised, controlled clinical trials and one prospective randomised, blinded clinical trial.

Strength of evidence

Weak.

Outcomes reported

Bupivacaine does not eliminate postoperative pain in cats undergoing ovariohysterectomies; minimal evidence was found to suggest that it was better at reducing postoperative pain scores in comparison to other analgesics. However, bupivacaine may provide analgesic benefits to cats when administered via intraperitoneal or subcutaneous injections as local anaesthesia and in combination with other analgesic agents. The need for postoperative rescue analgesia was minimised when bupivacaine was administered prior to or during the ovariohysterectomy.

Conclusion

When compared to a control, pain scores for the participating cats were lower after administration of bupivacaine, however, statistical significance was only reached in one of the studies. Additionally, other medications were found to lower the post operative pain score to a greater effect. However, bupivacaine administration is cheap and simple to perform, so it’s use as part of a multimodal analgesic protocol is supported. Confounding factors within the studies may have altered the perceived effectiveness of the analgesic properties of bupivacaine though, so further investigation involving larger cohorts with standardised controls would be prudent.

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 client is considering an ovariohysterectomy for their cat. They notice a fee for a bupivacaine local anaesthetic block and question the necessity of this. You review the evidence for the use of bupivacaine as part of a multi-modal anaesthetic protocol in cats undergoing elective ovariohysterectomy via ventral midline coeliotomy.

The evidence

All three studies followed a reliable method, appropriate to the category of research.  Each of the three studies consistently found that bupivacaine provided some level of analgesia in comparison to the saline / placebo measures. However, they were inconclusive in verifying bupivacaine’s superiority over other analgesics.

Unvalidated pain scales were used in all three studies which may have resulted in inaccurate representation of participant pain. Although the study’s individual methods were appropriate, combined use of validated and unvalidated pain scales may have impacted results drawn from the studies. Whilst statistical significance was only reached in one of the three studies, trend to lower pain scores in cats receiving bupivacaine was noted in all three.

Summary of the evidence

Benito et al. (2016a)

 

Fudge et al. (2020)

 

Tobias et al. (2006)

 

Appraisal, application and reflection

Three studies were found to be appropriate for this Knowledge Summary. They were all published in peer-reviewed journals and used prospective, controlled clinical trials. Benito et al. (2016a) and Tobias et al. (2006) implemented a blinded randomised method and Fudge et al. (2020) used a randomised double blinded placebo-controlled method. All three studies had approval from relevant bodies and the researchers ensured that all participants were provided additional rescue analgesia postoperatively, if required.

The first study analysed was Benito et al. (2016a), which included 45 client-owned cats of varying breeds. The use of client-owned participants increased the applicability of findings to general practice.

The requirement for rescue analgesia was significantly higher in the group receiving saline only compared to the groups receiving saline and meloxicam (P = 0.0004) or bupivacaine (P = 0.02). Of the saline group, 12/15 (80%) required further analgesia, compared to only 2/15 (13%) of the saline and meloxicam group, and 4/15 (27%) of the bupivacaine group. Whilst this shows that bupivacaine reduced patients’ pain scores and the need for further postoperative analgesia compared to the control, there was no statistically significant difference between the effectiveness of saline and meloxicam and the bupivacaine groups, suggesting that either protocol is appropriate.

Fudge et al. (2020) studied 212 cats from a shelter. Although a randomised study, the results were separated into different weight categories for each treatment group during data analysis to help with interpretation. All patients had an elevated pain score 1 hour postoperatively compared to discharge pain scores. Cats which received bupivacaine showed reduced pain scores compared to the two control groups (saline and sham controls) in all the weight brackets, however, the only statistical significance was found in the group weighing over 2.7 kg. It was found that cats both in the higher weight category and the bupivacaine group had a significantly lower pain score compared to the control groups 1 hour postoperatively (P = 0.008) and at discharge (P = 0.004). This implies that the effectiveness of bupivacaine may not be generalisable to all individuals due to weight related drug variations. However, the drug dosages were not specific to the patients’ exact weight, only to their weight category. This may have altered the significance of any difference in pain scores between the lower weight categories, and therefore should be considered when interpreting the significant data.

The third study, conducted by Tobias et al. (2006), assessed 52 client-owned cats. No sample size calculation was undertaken, which should be noted when making generalised assumptions from this study.

Baseline pain scores were taken using both chosen pain-scoring methods, and then repeated at intervals postoperatively. Participants who were given carprofen, ketoprofen, or bupivacaine had a significant increase in their pain scores, compared to the baselines (P ≤ 0.0122). These were recorded by both scoring methods at 1 and 2 hours postoperatively. Comparatively, those participants who received butorphanol had no significant change in their Visual Analogue Scale (VAS) scores, only a significant difference in the Interactive Visual Analogue Scale (IVAS) pain score 2 hours postoperatively (P = 0.0231). Additionally, participants from the bupivacaine group had higher postoperative pain scores compared to the other groups. Whilst this was only high enough in one participant to require rescue analgesia, it does suggest that there might be more beneficial analgesics to consider.

In general, these three main studies concluded that bupivacaine may have a clinical effect as an analgesic drug to reduce postoperative pain scores, however, statistical significance was not found in every study. This suggests that there was a possibility of the correlation between a bupivacaine local anaesthetic block and a reduced pain score being due to chance and other medications may be equally or even more effective in controlling postoperative pain.

Despite the similar generalised conclusions in the three main studies, there were some discrepancies between their findings. This suggests that a definitive conclusion cannot be drawn from these studies alone, without further research. Inconsistencies between methods, discussed below, may have contributed towards these differences in results.

The location of the local anaesthetic block was noted as a key difference in methodology, varying between studies. Benito et al. (2016a) and Fudge et al. (2020) administered the local anaesthetic in specific intraperitoneal locations, whereas Tobias et al. (2006) administered bupivacaine subcutaneously. This will have impacted the effect of the drugs and resulted in different nerves being blocked, hindering evaluation of the analgesic properties of bupivacaine.

Another variation to the methodologies was the chosen dose and dilution of bupivacaine. These variations may have indirectly resulted in the effectiveness of dose and dilution being evaluated, rather than the analgesic properties of bupivacaine. Benito et al. (2016a) used the lowest dilution of bupivacaine out of the three studies analysed. This chosen dilution was supported by research conducted by Benito et al. (2016b). Whilst it was found to be safe, the difference in dilution may hinder accuracy of the comparison between the three studies. Benito et al. (2016a) suggests that there is no difference between the analgesic properties of bupivacaine and their control medications, however, their findings may be reflective of the dilution rather than the analgesic properties of bupivacaine. Therefore, this needs to be considered when evaluating the effect on resulting pain scores.

Additionally, the chosen premedications varied throughout the studies. The studies either used acepromazine or dexmedetomidine as their chosen sedative. The duration of action for these two drugs is up to 6 hours and 20–60 minutes respectively , according to Ramsey, 2017. However, the duration of action of dexmedetomidine varies between sources, Granholm et al. (2006) found that heart rate and respiratory rate were still affected by dexmedetomidine over 3 hours after administration, indicating prolonged effects. Both acepromazine and dexmedetomidine had a risk of interfering with pain scores due to extended analgesic and sedative effects, possibly hindering the ability to infer analgesic properties of bupivicaine.

The analgesic effects of buprenorphine and ketamine should also be considered. The duration of action of these two drugs is up to 6 hours (Ramsey, 2017) and 20–40 minutes with a 1–4 hour recovery (NOAH, 2021). The duration of action of buprenorphine means it would have been active during most of the pain scores, the cats may also still have been recovering from the effects of ketamine. Additionally, ketamine can cause abnormal behaviour during recovery (Ramsey, 2017), which could hinder the process of pain evaluation.

Whilst it is important to recognise and understand the impact of premedication drugs, each study followed a standardised method throughout their data collection, therefore, producing valid results. Furthermore, the use of an opioid combined with a sedative drug is a routinely used premedication protocol in general practice (Murrell & Ford-Fennah, 2020). The premedications used are standard, applicable to a real-life setting and thus appropriate as administered in these studies.

A fourth key difference affecting comparison between the methods of the studies were the pain scoring systems used (figure 1). Benito et al. (2016a) used the Dynamic and Interactive Visual Analogue Scale (DIVAS) and UNESP-Botucatu Multidimensional composite pain scale (MCPS. Fudge et al. (2020) started with the latter, however many of the participants were feral, reducing application to practice and the ability to fully complete the scale. They switched to the Modified Colorado State University Feline Acute Pain Scale (mCSU) and Numerical Rating Scale (NRS). This change in pain scoring system reduced the palpation of the surgical site, and therefore the potential for staff injury. Tobias et al. (2006) employed the Visual Analogue Scale (VAS) and Interactive Visual Analogue Scale (IVAS), allowing for numerical and observational assessment.

Despite repeated use within the veterinary industry (Bloor, 2017), most of the pain scales used are not validated for cats. This should be considered when evaluating the reliability of the results, as they may have led to an inaccurate representation of participant pain. Issues with the reliability of pain scales were present in Fudge et al (2020), where the first phase of the study was disregarded due to significant difference between NRS and MCPS pain scores. NRS scores were higher than MCPS scores. The differences in scores were deemed as bias and therefore produced unreliable data for the study. However, the second phase of Fudge et al (2020)’s study replaced the validated MCPS scale with the mCSU, an unvalidated scale for use in cats. Therefore, the results are based on two unvalidated pain scales, and the results from phase one suggest they may have produced inaccurately high pain scores. The supposed bias should have been noted to highlight the possible inaccuracies of an unvalidated pain scale. These inaccuracies may also be reflected in the results of Tobias et al (2006), as they also only used unvalidated pain scales during their study.

The blinded nature of the study designs is expected to reduce bias, allowing for honest observations, without any preconceptions or opinions swaying the results (Moustgaard et al., 2020). In addition, all assessors throughout the three studies were trained to conduct the pain scores, which may have improved interobserver agreement.

 

Abbreviation	Pain scale	Validated for feline patients?	Method of assessment	Which studies used which scoring system?
(DIVAS)	Dynamic and interactive visual analogue scale	No	Visualising pain using a 10cm line (each cm represents a score). 0–10 scale (0 = no pain, 10 = high pain).	Benito et al. (2016a) &  Fudge et al. (2020) started with MCPS but altered their method
(MCPS)	UNESP-Botucatu Multidimensional composite pain scale	Yes	Emotional and physical effects of pain. Multiple behavioural categories are scored, equaling an overall score.
(mCSU)	Modified Colorado State University Feline Acute Pain Scale	No	Removed palpation of surgical site. Multidimensional scale which uses behavioural cues to assess pain.	Fudge et al. (2020)
(NRS)	Numerical Rating Scale	No	The observer assigns a score of pain from 0–10 (0 = no pain, 10 = high pain).
(VAS)	Visual Analogue Scale	No	Visualising pain using a 10 cm line (each cm represents a score). 0–10 scale (0 = no pain, 10 = high pain).	Tobias et al. (2006)
(IVAS)	Interactive Visual Analogue Scale	No	Visualising pain using a 10 cm line (each cm represents a score). 0–10 scale.

 

Figure 1. Table showing the pain scales used in the studies.

 

The timing of pain scoring was the final methodology difference analysed. Bupivacaine has an initial onset time of 2 and 5 minutes, with full block normally occurring between 5–10 minutes (Grubb & Lobprise, 2020). All postoperative pain scores were taken after this onset time and within bupivacaine’s duration of action. However, within the study by Fudge et al. (2020), postoperative pain scores were taken 1 hour into recovery and at discharge. Discharge times ranged from 1.7–7 hours post anaesthesia; therefore, some scores would have been taken close to the end of bupivacaine's duration of action, possibly reducing analgesic effects. This could have influenced the ability of pain scores to accurately assess the effect of bupivacaine at this timepoint.

Since evaluation of these three studies, Fudge et al. (2021) has published further research, comparing the use of bupivacaine with other targeted intraoperative injections (bupivacaine-lidocaine-epinephrine, dexamethasone, meloxicam). They conducted a prospective, randomised, double-blinded clinical trial with 151 cats, all undergoing midline ovariohysterectomies. The research followed similar guidelines to Fudge et al. (2020) but aimed to see if other drugs administered as targeted injections provided more effective analgesia than bupivacaine, like Tobias et al. (2006). Using the 0–10 Numerical Rating Scale (NRS), they found no statistical significance in postoperative pain scores between any of the groups 1 hour post-anaesthesia. Whilst meloxicam showed lower post-operative pain scores at 3 hours post-anaesthesia compared to all groups, it only gained statistically significant lower scores than the bupivacaine-lidocaine-epinephrine group (P = 0.018). Fudge et al. (2021) concluded that all of the tested drugs performed similarly as part of multimodal analgesia for feline ovariohysterectomies, except for meloxicam which may lower pain scores more than the bupivacaine-lidocaine-epinephrine block.

Similarly, Benito et al. (2019) conducted a study following Benito et al. (2016a), aiming to determine if administering bupivacaine with dexmedetomidine would provide superior analgesia in comparison to bupivacaine alone, when given to cats via splash block during ovariohysterectomy. This time Benito et al. (2019) used the UNESP-Botucatu composite pain scale to evaluate postoperative pain. They found that median pain scores in cats receiving just bupivacaine were significantly higher than those receiving bupivacaine and dexmedetomidine (P = 0.023) at 12 hours post-surgery, suggesting that administering bupivacaine along with another analgesic may reduce postoperative pain scores. Prior to this study, Benito et al. (2018) investigated the efficacy and pharmacokinetics of bupivacaine given in combination with epinephrine or dexmedetomidine to cats undergoing ovariohysterectomies. Results found that both drug combinations provide similar analgesic effects.  Although this study does not fit the PICO question for this Knowledge Summary due to the absence of testing bupivacaine alone, its conclusions support the use of bupivacaine in conjunction with another drug.

Furthermore, there may also be other alternative forms of bupivacaine which could be more favourable. Bupivicaine liposome injectable suspension is a longer lasting lipid based injectable that has a prolonged analgesic effect (Gordon-Evans et al., 2020). Although it is not directly comparable to bupivacaine hydrochloride and is not yet available globally, it may be another option to explore in the future.

Generalised findings conclude that a bupivacaine local anaesthetic block may influence post-operative pain in cats undergoing ovariohysterectomies, reducing the need for rescue analgesia. The technique of administering bupivacaine requires minimal skill to perform and is cost effective (Fudge et al., 2020).  However, further research is required to assess a range of other medication combinations, to ensure that the method is not only used because it is cheap and easy, but also effective and warranted. Research suggests that use of bupivacaine in conjunction with other analgesics may be preferable, but this should be explored further. Use of validated pain scales such as the Glasgow composite measure pain scale (WSAVA, 2015) and the incorporation of an objective assessment method such as the mechanical nociceptive threshold probe used by Benito et al. (2016a) could improve future research, although may be challenging with more aggressive patients. Conducting prospective randomised double blinded placebo-controlled clinical trials on different analgesics and locations could fill an evidence gap currently present.

Methodology

Search Strategy

 

Exclusion / Inclusion Criteria

 

Search Outcome

 

Author contributions

Tara Freeman: Conceptualisation, Investigation, Resources, Writing – Original draft, Writing – Review & Editing (lead). Amelia Wisby: Conceptualisation, Investigation, Resources, Writing – Original draft. Kate Burroughs: Conceptualisation, Investigation, Resources, Writing – Original draft. Samantha Gentle: Conceptualisation, Investigation, Resources, Writing – Original draft. Connie Ellis: Conceptualisation, Investigation, Resources, Writing – Original draft. Sarah Batt-Williams: Supervision.

ORCID

Tara Freeman: https://orcid.org/0000-0002-5588-9623
Kate Burroughs: https://orcid.org/0000-0003-4062-2739
Connie Ellis: https://orcid.org/0000-0002-3305-6866
Sarah Batt-Williams: https://orcid.org/0000-0001-8713-6944

Conflict of Interest

The authors declare no conflicts of interest.

References

1. Benito, J. Evangelista, M.C., Doodnaught, G.M., Watanabe, R., Beauchamp, G., Monteiro, B.P. & Steagall, P. (2019). Analgesic efficacy of bupivacaine or bupivacaine-dexmedetomidine after intraperitoneal administration in cats: A randomised, blinded, clinical trial. Frontiers in Veterinary Science. 13(6). DOI: https://doi.org/10.3389/fvets.2019.00307
2. Benito, J., Monteiro, B., Beaudry, F. & Steagall, P. (2018). Efficacy and pharmacokinetics of bupivacaine with epinephrine or dexmedetomidine after intraperitoneal administration in cats undergoing ovariohysterectomy. The Canadian Journal of Veterinary Research. 82(2), 124–130.
3. Benito, J., Monteiro, B., Lavoie, A., Beauchamp, G., Lascelles, B.D. & Steagall, P. (2016a). Analgesic efficacy of intraperitoneal administration of bupivacaine in cats. Journal of Feline Medicine and Surgery. 18(11), 906–912. DOI: https://doi.org/10.1177/1098612x15610162
4. Bento, J., Monteiro, B.P., Beaudry, F., Lavoie, A., Lascelles, B.D. & Steagall, P.V. (2016b). Pharmacokinetics of bupivacaine after intraperitoneal administration to cats undergoing ovariohysterectomy. American Journal of Veterinary Research. 77(6), 641–645. DOI: https://doi.org/10.2460/ajvr.77.6.641
5. Bloor, C. (2017). Pain scoring systems in the canine and feline patient. The Veterinary Nurse. 8(5), 252–258. DOI: https://doi.org/10.12968/vetn.2017.8.5.252
6. Brondani, J.T., Mama, K.R., Luna, S.P.L, Wright, B.D., Niyom, S., Ambrosio, J., Vogel, P.R. & Padovani, C.R. (2013). Validation of the English version of the UNESP-Botucatu multidimensional composite pain scale for assessing operative pain in cats. BMC Veterinary Research. 9(1), 143. DOI: https://doi.org/10.1186/1746-6148-9-143
7. Fudge, J.M., Page, B. & Lee, I. (2021). Evaluation of targeted bupivacaine, bupivacaine-lidocaine-epinephrine, dexamethasone, and meloxicam for reducing acute postoperative pain in cats undergoing routine ovariohysterectomy. Topics in Companion Animal Medicine. 45(NOV 2021). DOI: https://doi.org/10.1016/j.tcam.2021.100564
8. Fudge, J.M., Page, B., Mackrell, A. & Lee, I. (2020). Evaluation of targeted bupivacaine for reducing acute postoperative pain in cats undergoing routine ovariohysterectomy. Journal of Feline Medicine and Surgery. 22(2), 91–99. DOI: https://doi.org/10.1177/1098612X19826700
9. Gordon-Evans, W. J., Suh, H. Y. & Guedes, A. G. (2020). Controlled, non-inferiority trial of bupivacaine liposome injectable suspension. Journal of Feline Medicine and Surgery. 22 (10). DOI: https://doi.org/10.1177/1098612X19892355
10. Granholm, M., McKusick, B., Westerholm, F.C. & Aspegren, J.C. (2006). Evaluation of the clinical efficacy and safety of dexmedetomidine or medetomidine in cats and their reversal with atipamazole. Veterinary Anaesthesia and Analgesia. 33(4), 214–223. DOI: https://doi.org/10.1111/j.1467-2995.2005.00259.x
11. Grubb, T. & Lobprise, H. (2020). Local and regional anaesthesia in dogs and cats: Overview of concepts and drugs (Part 1). Veterinary Medicine and Science. 6(2), 209–217. DOI: https://doi.org/10.1002/vms3.219
12. Moustgaard, H., Clayton, G., Jones, H., Boutron, I., Jørgensen, L., Laursen, D., Olsen, M., Paludan-Müller, A., Ravaud, P., Savović, J., Sterne, J., Higgins, J. & Hróbjartsson, A. (2020). Impact of blinding on estimated treatment effects in randomised clinical trials: meta-epidemiological study. BMJ. 368(8230). DOI: https://doi.org/10.1136/bmj.l6802
13. Murrel, J. & Ford-Fennah, V. (2020). Anaesthesia and analgesia’, in Cooper, B., Mullineaux, E. and Turner, L., BSAVA Textbook of veterinary nursing, 6^th ed., Gloucester: British Small Animal Veterinary Association, 669–747.  
14. NOAH. (2021). Welcome to the NOAH Compendium. [online]. Available from: https://www.noahcompendium.co.uk/?id=-312863 [Accessed September 2022].
15. Ramsey, I. (2017). Small Animal Formulary, 9th ed., England: British Small Animal Veterinary Association.
16. Shipley, H., Guedes, A., Graham, L., Goudie-DeAngelis, E. & Wendt-Hornickle, E. (2018). Preliminary appraisal of the reliability and validity of the Colorado State University Feline Acute Pain Scale. Journal of Feline Medicine and Surgery. 21(4), 335–339. DOI: https://doi.org/10.1177/1098612X18777506
17. Tobias, K.M., Harvey, R.C. & Byarlay, J.M. (2006). A comparison of four methods of analgesia in cats following ovariohysterectomy. Veterinary Anaesthesia and Analgesia. 33(6), 390–398.  DOI: https://doi.org/10.1111/j.1467-2995.2005.00282.x
18. WSAVA. (2015). Feline composite pain scale. [online]. Available from: https://wsava.org/wp-content/uploads/2020/01/Feline-CMPS-SF.pdf [Accessed September 2022].

---