KNOWLEDGE SUMMARY

Keywords: ANALGESIA; BUPRENORPHINE; CAT; FELINE; METHADONE; OVARIOHYSTERECTOMY; PAIN; SPAY

Methadone or buprenorphine: which is the better analgesic for feline ovariohysterectomy?

Isobel Lawrence, BVSc MRCVS^1*

¹ University of Liverpool, United Kingdom
* Corresponding author email: isobellawrence12@gmail.com

Vol 9, Issue 4 (2024)
Submitted: 12 Jan 2024; published: 12 Nov 2024; next review: 06 Jan 2026
DOI: https://doi.org/10.18849/ve.v9i4.704

PICO question

In female cats undergoing routine ovariohysterectomy, is using methadone, compared to buprenorphine, in the anaesthetic protocol associated with lower postoperative pain scores?

Clinical bottom line

Category of research

Treatment.

Number and type of study designs reviewed

Four assessor-blinded randomised controlled trials.

Strength of evidence

Moderate.

Outcomes reported

Two studies found methadone to be associated with significantly lower postoperative pain scores than buprenorphine; one showed significantly different pain scores over the entire 8-hour postoperative period and one only at 10 minutes postextubation. One study found buprenorphine to be associated with lower postoperative pain scores at some time points postsurgery. One study found no significant difference in pain scores between methadone and buprenorphine.

Conclusion

It can be concluded that using methadone in the anaesthetic protocol may provide better analgesia for cats undergoing ovariohysterectomy compared to buprenorphine. The two papers that used validated pain scoring both concluded that methadone was associated with lower pain scores at some points postoperatively. Although one of the studies concluded that buprenorphine is associated with lower postoperative pain scores, this paper provides only very weak evidence because an unvalidated pain scoring method was used. More evidence is needed to confidently recommend using one opioid over another.

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

Feline ovariohysterectomies are some of the most commonly performed surgeries in first opinion veterinary practice. These may be owned animals, but they may also be CNVR (catch, neuter, vaccinate, release) situations where the cat will not be given any further analgesia after discharge; therefore, it is imperative that perioperative analgesia is effective. Opioids are often used in the anaesthetic protocol because they provide reliable analgesia, can be reversed, and have a wide safety margin in cats. However, the choice of opioid often varies between clinicians.

Historically, pain in cats has been undertreated due to signs of pain being difficult to identify in this species, and the ability of cats to mask signs of pain (Steagall & Monteiro, 2019; Steagall et al., 2022). This is an issue because inadequate management of acute, perioperative pain can lead to chronic pain and central sensitisation (Monteiro et al., 2023). The development of several validated feline pain scales, including the UNESP-Botucatu multidimensional composite pain scale (Brondani et al., 2013), the Glasgow Feline Composite Measure Pain Scale (CMPS-F) (Reid et al., 2017), and the Feline Grimace Scale (Evangelista et al., 2019), have allowed us to better assess pain in cats, and are commonly used in the studies that this Knowledge Summary evaluates.

Methadone, buprenorphine, and butorphanol are the most commonly used opioids in feline anaesthetic protocols. Butorphanol has a short duration of action and provides mild analgesia, insufficient for surgical procedures (Warne et al., 2014). This Knowledge Summary investigates the difference in postoperative pain scores when methadone is used in the anaesthetic protocol for routine ovariohysterectomy, compared to when buprenorphine is used. Methadone is a synthetic mu agonist which is a racemic mixture of d and l enantiomers. The d enantiomer also has effects on NMDA (N-methyl-d-aspartate) receptors providing an alternative analgesic pathway. Buprenorphine is a semi-synthetic partial μ-opoid agonist (Bortolami & Love, 2015). In the clinical setting this Knowledge Summary will help the clinician decide whether to use methadone or buprenorphine to provide the most reliable analgesia for our feline patients.

The evidence

A search of the literature returned four studies that were relevant to this PICO. All four studies are assessor-blinded randomised controlled trials directly comparing postoperative pain scores between methadone and buprenorphine.

Although all studies evaluated are randomised controlled trials and therefore are at the same level on the hierarchy of evidence, there is variation in the strength of evidence provided by each study. The study by Shah et al. (2019) provides the strongest evidence as the sample size exceeds the power calculation, validated pain scoring methods are used, and cats were evaluated for a suitable amount of time postoperatively. The study by Mahdmina et al. (2020) provides a weaker level of evidence because the sample size does not meet the target set by the power calculation and cats were only evaluated for 30 minutes postextubation; however, it also used validated pain scoring methods. The studies by Bortolami et al. (2013) and Slingsby et al. (2014) provide the weakest evidence because they use unvalidated pain scoring methods and the sample size when just looking at female cats is too small. Overall, the strength of evidence is moderate.

Summary of the evidence

Bortolami et al. (2013)

 

Mahdmina et al. (2020)

 

Shah et al. (2019)

 

Slingsby et al. (2014)

 

Appraisal, application and reflection

The aim of this Knowledge Summary was to critically appraise the existing evidence to determine whether methadone or buprenorphine is a better postoperative analgesic for cats undergoing ovariohysterectomy. A search of the literature returned four papers that were relevant to the PICO (Shah et al., 2019; Mahdmina et al., 2020; Slingsby et al., 2014; Bortolami et al., 2013). All four papers were assessor-blinded randomised controlled trials that directly compared postoperative pain scores in cats receiving buprenorphine or methadone. Two of the studies (Bortolami et al., 2013; Slingsby et al., 2014) also compared butorphanol which will not be discussed further in this Knowledge Summary. The same two studies also had male cats in the treatment groups; however, because the pain scores from the males and females were presented separately, it was possible to just analyse the pain scores from female cats undergoing ovariohysterectomy.

All studies reported that both buprenorphine and methadone provided adequate analgesia for ovariohysterectomy in cats; however, some papers reported significant differences in pain scores postoperatively. Shah et al. (2019) reported that although Glasgow Composite Measure Pain Scale – Feline (CMPS-F) scores were not significantly different at any one time, over time the cats receiving methadone had a significantly lower CMPS-F score compared to the cats receiving buprenorphine. This led to significantly more rescue analgesia in the group receiving buprenorphine. Mahdmina et al. (2020) also found methadone to have an advantage over buprenorphine as dynamic interactive visual analogue scale (DIVAS) pain scores were significantly higher in the group receiving buprenorphine than the group receiving methadone 10-minutes postsurgery. However, there were no significant differences in the three other pain scores used or at any other time point. In contrast, Slingsby et al. (2014) found that buprenorphine was associated with lower postoperative interactive visual analogue scores (IVAS) than methadone at 3, 4, and 6 hours after premedication when pain scores were corrected for rescue analgesia. Finally, Bortolami et al. (2013) found no significant differences in IVAS pain scores between methadone and buprenorphine at any time after premedication.

In all studies the person pain scoring the cats was the same and was blinded to treatment group, however the pain scoring methods utilised differed between studies. The two older studies (Bortolami et al., 2013; Slingsby et al., 2014) used IVAS pain scoring. IVAS pain scoring is an unvalidated system and the scores are often highly variable. In comparison, the two newer studies (Mahdmina et al., 2020; Shah et al., 2019) both used a combination of validated and unvalidated pain scoring systems with Mahdmina et al. (2020) using simple descriptive scale (SDS), numeric rating scale (NRS), DIVAS and UNESP-Botucatu multidimensional composite pain scale and Shah et al. (2019) using DIVAS and CMPS-F. Even though the validated systems are still subjective measures of pain, they have been tested to confirm their validity, sensitivity, and reliability, and therefore the results can be relied upon far more than the non-validated systems (Steagall and Monteiro, 2019). Therefore, the studies in this Knowledge Summary that use validated scoring systems provide stronger evidence (Mahdmina et al., 2020; Shah et al., 2019), and the findings are more reliable than the studies that do not (Bortolami et al., 2013; Slingsby et al., 2014).

Even when using validated scoring systems, pain assessment in cats presents many challenges. Animals that have a shy, fearful, or aggressive demeanor are often given higher pain scores. This can be a problem in a hospital environment where cats often present with behavioral changes because they are stressed (Steagall & Monteiro, 2019). Furthermore, it is challenging to differentiate between pain and dysphoria. This is particularly relevant in this Knowledge Summary as patients recovering from anaesthesia who have received opioids can often be very dysphoric. This would lead to an inflation of pain scores. This raises the question as to whether pain scoring is a sensitive enough tool to evaluate the efficacy of analgesia, and whether more objective measures such as mechanical nociceptive threshold testing would provide a more reliable conclusion.

The other main thing that varied between these studies was at what point the NSAID was administered. In general practice the NSAID is usually given at the time of premedication or intraoperatively as this provides multimodal analgesia, which has been shown to be more effective (Steagall et al., 2022). However, in these studies there was a judgement to be made on whether to give the NSAID later so that any differences in pain scores between the methadone and buprenorphine were more likely to be identified or give it at the same time as the premedication because it would be easier to extrapolate the results of the study to a general practice situation. Mahdmina et al. (2020) was the only study reviewed that gave the NSAID at the time of premedication. The other studies (Shah et al., 2019; Bortolami et al., 2013; Slingsby et al., 2014) either gave the NSAID at 6 or 8 hours after premedication. This means that the results of these studies may be less comparable to general practice. Moreover, in the study by Mahdmina et al. (2020) the doses of meloxicam given to the cats in the methadone and buprenorphine groups were different with the cats who received methadone getting 3 mg/m².

On the other hand, the studies undertaken by Bortolami et al.(2013) and Slingsby et al.(2014) may be more comparable to general practice because they performed flank ovariohysterectomies in the study, Shah et al. (2019) and Mahdmina et al. (2020) both performed midline ovariohysterectomies. In the UK the majority of cats are neutered via the flank approach as it is less invasive and associated with fewer wound infections (Munif, Safawat & Abdul, 2022). Flank ovariohysterectomies are associated with a greater level of pain than midline ovariohysterectomies because the incision is made through muscle tissue rather than the linea alba. Muscle has more nociceptors that connect to Aδ and C fibres than the linea alba which results in more nociception and pain (Grint et al., 2006). This may limit how easy it is to extrapolate the results of the studies that performed midline ovariohysterectomies to UK general veterinary practice. Unfortunately, these studies are also the ones that used validated pain scoring methods. Therefore, to draw conclusions that were more useful for UK first opinion practice, more studies using the validated pain scoring methods would be needed where flank ovariohysterectomies were performed.

Sample size targets were calculated in every study; however, these were not always reached. Mahdmina et al. (2020) calculated that 50 cats were needed; however, only 41 cats finished the study. In Shah et al. (2019), the necessary sample size was calculated to be 58, which was exceeded, as 120 cats were recruited and all cats finished the study. In both the Bortolami et al. (2013) and Slingsby et al. (2014) the target sample sizes were both 30, and the actual number of cats in each study was 45. However, both studies also included male cats, meaning the number of female cats in each study was only 24. This means that not only were these studies underpowered for this Knowledge Summary, but considering males had low pain scores and were deemed a poor surgical model, it also means that this study in general was underpowered to detect differences between groups. It is possible that the lack of significant difference in pain scores between the cats receiving methadone and the cats receiving buprenorphine was actually due to there not being enough cats in the studies, leading to a type II statistical error, rather than there not being a difference in analgesia provided. Interestingly, the study with the most consistent differences in pain scores over the whole postoperative period (Shah et al., 2019) was also the study that massively exceeded the sample size predicted by the power calculation. This indicates the need for more research using bigger sample sizes.

The length of time that cats were pain scored for postoperatively varied between studies. One study only recorded pain scores up to 30 minutes postextubation to determine whether rescue analgesia was needed (Mahdmina et al., 2020). This may have been too soon after extubation to allow the cat to recover and start showing signs of pain, because no cats in this study required rescue analgesia. The 2022 International Society of Feline Medicine (ISFM) consensus guidelines on management of acute pain suggest waiting for 45 minutes postoperatively and continuing pain assessments until discharge (Steagall et al., 2022). By pain scoring for a longer period postoperatively it would have given a better assessment of the duration of action and efficacy of the two opioids. The other three studies monitored pain scores up to 8 hours after premedication to determine whether rescue analgesia was needed (Shah et al., 2019; Bortolamiet al., 2013; Slingsby et al., 2014). In all these studies some patients required rescue analgesia which demonstrates the importance of pain scoring for a longer duration postoperatively.

In all studies the cats were of mixed ages, however the mean age was not significantly different between the groups receiving buprenorphine or methadone. This ensures that age was not a confounding factor in the studies reviewed. Table 1 below gives the mean age of cats for each of the studies. By studying a mix of ages it also means that any conclusions that we can draw assume that the efficacy of analgesia is the same in cats of all ages. However, research has shown that more frequent opioid dosing may be necessary in young cats. One study showed that the age of the cat can affect thermal antinociception produced by opioids (Steagall et al., 2022). This is particularly noteworthy because the recommended age of neutering in cats is from 4 months (The Cat Group, 2006) and many of the studies reviewed here have mean ages greater than 4 months (see table 1). This may limit how well the results of these studies can be extrapolated to UK veterinary practice. Therefore, more studies are warranted to see whether there may be a difference in analgesic efficacy, between buprenorphine and methadone, in specific age groups.

Table 1: average age in months of the cats in each study. Where the study gave the ages separately for each opioid group, this is specified in the table.

Study	Mean and range of ages of cats in the study (months)
Shah et al. (2019)	Buprenorphine group: 16.2 ± 14.4 Methadone group: 13.3 ± 9.46
Mahdmina et al. (2020)	Buprenorphine group: 12 (3–48) Methadone group: 14 (2–48)
Bortolami et al. (2013)	7 ± 4 (not presented by opioid group)
Slingsby et al. (2014)	8.7 ± 5.1 (not presented by opioid group)

The current evidence demonstrates that both buprenorphine and methadone provide adequate analgesia in cats undergoing ovariohysterectomy. In the studies that used validated pain scoring methods (Mahdmina et al., 2020; Shah et al., 2019) and therefore, the more reliable studies, methadone was found to be associated with lower pain scores overall, or at selected time points postoperatively. Therefore, it can be concluded that there is moderate evidence to suggest methadone is a better analgesic for feline ovariohysterectomy than buprenorphine. Future research should focus on making use of the three validated pain scoring systems that are now available and use large enough sample sizes. To be able to better extrapolate the results to UK veterinary practice it would also be useful to have more studies focusing on flank ovariohysterectomies in cats around 16 weeks of age. Ultimately this Knowledge Summary highlights the importance of using validated postoperative pain scoring in general practice to identify cats who require additional analgesia.

Methodology

Search strategy

 

Exclusion / inclusion criteria

 

Search outcome

 

ORCiD

Isobel Lawrence: https://orcid.org/0009-0009-6087-7043

Conflict of interest

The author declares no conflicts of interest.

References

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