Does trazodone reduce anaesthetic agent requirement in dogs?

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Appraisal, application and reflection

The randomised controlled trials appraised are designed appropriately to address the PICO question (EBVM Network, 2021). Hoffman et al. (2018) used no treatment as a comparator and Murphy et al. (2017) used a recognised premedication acepromazine as a comparator. The level of evidence appraised is level two based on the Oxford Centre for Evidence-based Medicine Levels of Evidence (CEBM, 2009) which provides fairly robust evidence towards answering the PICO question. There is no higher level of evidence published that was suitable to answer the PICO question. Both studies are based on objective assessments. Randomly allocating the treatment group reduces potential bias from allocation and with the observer.

The evidence appraised demonstrates trazodone provides an isoflurane minimum alveolar concentration (MAC) sparing effect in anaesthetised dogs (Hoffman et al., 2018) and has similar cardiovascular effects to acepromazine in anaesthetised, healthy dogs (Murphy et al., 2017). Hoffman et al. (2018) provides supporting evidence that trazodone does reduce the MAC of isoflurane reported as 1.02 ± 0.11% reducing to 0.85 ± 0.17% with the addition of trazodone to the protocol (p = 0.01, 95% confidence interval -0.25–^-0.05). Murphy et al. (2017) could find no significant differences between trazodone and acepromazine, a strong comparator which has been shown independently to have a MAC sparing effect (Monteiro et al., 2016). However, there were multiple confounding factors which may have influenced the results. Primarily, this study reported on the reduction in propofol dose required for induction of anaesthesia. No difference was found between the acepromazine and trazodone groups of patients. Acepromazine has been shown to reduce the propofol dose required for the induction of anaesthesia (Dantino et al., 2021), therefore trazodone may have a similar effect, although difficult to determine due to confounding factors of varied acepromazine doses and rate of propofol administration. Acepromazine is known to have a reducing effect on blood pressure in dogs (Grasso et al., 2015), therefore by having no significant difference in cardiovascular variables, trazodone may also have an impact on blood pressure. Results demonstrated by Hoffman et al. (2018) show that blood pressure and heart rate were similar in cases that had received trazodone or higher levels of isoflurane, which would suggest trazodone could have cardiovascular effects.

Both papers accounted for all of the animals included in the trial in the conclusion. Hoffman et al. (2018) report results from all of the animals included in the trial. Murphy et al. (2017) state some of the participants in their trial were excluded from the results, mostly because a standardised protocol was not used throughout the procedure, for example the use of isoflurane (n = 28) versus sevoflurane (n = 2). Hoffman et al. (2018) used a crossover design to the study, enabling a direct comparison between interventions in all participants. Other than the intervention and the comparator, the groups were treated equally in both studies appraised.

There are limitations to the research available. Inclusion and exclusion factors are well defined in both papers, but participants are not fully representative of all patients undergoing the multitude of procedures performed in practice. Whilst they are of the correct species, the evidence focuses solely on systemically healthy dogs. Potential candidates with concurrent disease were excluded from both studies, limiting the application of the research in clinical practice where many of the patients suffer with concurrent disease, highlighting an area for further research. There are weaknesses in the Murphy et al. (2017) study design, despite being a randomised control trial, that limit the conclusions drawn from the research. No control was used for comparison meaning it cannot be determined whether or not trazodone reduced the quantity of propofol required for the induction of anaesthesia. The comparator, acepromazine, had a 200% variation in dose at the discretion of the anaesthetist, affecting the validity of the results obtained by comparison.

Further research would be desirable to improve the external validity of the evidence presented. The multiple variables that could be influencing the results in the Murphy et al. (2017) study’s conclusion that there are no significant differences between acepromazine and trazodone are concerning and affect the level of reliability of the results. Hoffman et al. (2018) do provide reliable results although on a small scale with a narrower population demographic.

All of the evidence appraised is based on a single dose of orally administered trazodone 2 hours before the induction of anaesthesia, administered in the clinical setting. As an anxiolytic drug, if administered ahead of the stressor that is travelling and visiting a veterinary practice the effects may be improved and provide a more practical approach to the administration of trazodone as part of a pre-anaesthetic protocol. Hoffman et al. (2018) used an 8 mg/kg dose 2 hours before the induction of anaesthesia and Murphy et al. (2017) used a 5–7 mg/kg dose depending on body weight. The BSAVA formulary stated dose for use in dogs to treat chronic anxiety is ‘5–10 kg, 25 mg p.o. q24h; 11–20 kg, 50 mg p.o. q24h; >21 kg, 100 mg p.o. q24h’ (Ramsey, 2017). Jay et al. (2013) report the time to maximum plasma concentration following oral administration as 445 minutes ± 271 minutes which would mean the 2 hours allowed prior to induction would be inadequate. This could also be problematic when considering adding trazodone as part of premedication as to reach maximum plasma concentration, it would need to be administered 7.5 hours before induction.

Beneficial effects of the treatment were identified and no significant adverse effects were noted with the administration of trazodone when compared with no intervention or acepromazine. Murphy et al. (2017) reported one dog experienced priaprism 24 hours post administration of trazodone which was resolved with treatment, this is a rare side effect also noted in humans (Abber et al., 1987). Trazodone has been shown to reduce stress in postoperative patients (Gruen et al., 2014). This could be extrapolated to patients confined ahead of anaesthesia, who may therefore require less anaesthetic agents to induce and maintain a suitable depth of anaesthesia. There could be an argument for combining it as part of a multimodal approach to the pre-anaesthetic protocol, however, the reported MAC reduction of trazodone is less than other agents such as alpha-2-agonists (Sinclair, 2003) or opioids (Credie et al., 2010).

In conclusion, there is some strong evidence to support the intervention of trazodone to reduce the dose of inhalant anaesthetic agent administered. Consideration must be taken regarding the use of the cascade due to lack of licensing and the potential for only a modest reduction in MAC. Administration orally 2 hours before the induction of anaesthesia, may be an inadequate time to reach maximum effect. Further research would be beneficial to establish a stronger argument for the inclusion of trazodone in a multimodal anaesthetic protocol.

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