Comparison of the effects of buprenorphine and methadone in combination with medetomidine followed by intramuscular alfaxalone for anaesthesia of cats undergoing ovariohysterectomy

Abstract

Objectives

The aim of this study was to compare the quality of anaesthesia and analgesia between methadone and buprenorphine in combination with medetomidine after induction with intramuscular (IM) alfaxalone in cats undergoing ovariohysterectomy.

Methods

Fifty-one female cats (American Society of Anesthesiologists status I–II), with a median age of 12 months (range 2–60 months), weighing a mean ± SD of 2.5 ± 0.5 kg, were recruited to the study. Cats were randomly allocated to receive medetomidine (600 µg/m²) and buprenorphine (180 µg/m²) (group MB) or medetomidine (500 µg/m²) and methadone (5 mg/m²) (group MM) IM. Anaesthesia was induced 15 mins later using alfaxalone (3 mg/kg) IM. Anaesthesia was maintained with isoflurane in oxygen. All cats received meloxicam preoperatively. Quality of premedication and induction and intraoperative physiological parameters were recorded. Atipamezole (50% of medetomidine dose) was administered at the end of surgery. Cats were assessed postoperatively by the same blinded observer using a simple descriptive scale, numeric rating scale, dynamic interactive visual analogue scale (DIVAS) and UNESP-Botucatu multidimensional composite pain scales, at 10, 20 and 30 mins post-extubation. Parametric and non-parametric data were compared using Student’s t-test or Mann–Whitney U-tests, respectively.

Results

Forty-one cats completed the study. No significant differences were detected between groups before or during anaesthesia. No cats required rescue analgesia. DIVAS scores at 10 mins were significantly less in the MM group compared with the MB. No differences between groups at any other time points were detected using the four metrology instruments.

Conclusions and relevance

Both protocols provided good anaesthesia conditions for ovariohysterectomy in the cat.

Keywords

Alfaxalone anaesthesia buprenorphine methadone ovariohysterectomy spay

Introduction

Ovariohysterectomy (OVH) in cats is a routine surgical procedure carried out in private veterinary practices and animal shelters in the UK.^1,2 In a shelter environment especially, cats of an array of ages (including young kittens) and temperaments (including feral animals) are commonly admitted, many with little or no prior clinical history.¹ Physical restraint and intravenous (IV) access may be limited, making intramuscular (IM) administration of anaesthetic drugs preferable.

Sedation and analgesia

There are several existing drug combinations commonly used for IM feline anaesthesia. In the case of feral and shelter animals, there is a need for a profound level of sedation, in order to allow a thorough examination prior to neutering. Medetomidine is reported to have a sparing effect on dosage of induction agents and was the drug of choice in this study.³ The addition of an opioid to the combination can further reduce induction agent dosage while providing profound and long-lasting perioperative analgesia.^4–8 Perioperative analgesia is especially important given OVH has been described by Mathews et al as causing moderate pain to the patient depending on the degree of surgical trauma.^9,10 In this study, the sedative and analgesic effects of buprenorphine and methadone were investigated.

Anaesthesia

Alfaxalone is a synthetic neuroactive steroid, with market authorisation in the UK for IV but not IM administration. The preparation is licensed for the IM route in Australia, New Zealand and South Africa.¹¹ Following IV administration, a number of studies have found minimal impact on the cardiorespiratory system and provision of smooth inductions and fast recoveries.^12–16 However, Mathis et al observed a greater frequency of paddling and trembling during the recovery period following alfaxalone induction than with propofol induction. Few studies have investigated alfaxalone as an IM induction agent in cats.^17–19 Only one of these was for use for an invasive procedure (castration),¹⁷ while another included minor procedures only.¹⁸

The aims of this study were to compare the quality of anaesthesia and analgesia between methadone and buprenorphine in combination with medetomidine prior to induction of anaesthesia with IM alfaxalone.

Materials and methods

This study took place at the RSPCA Greater Manchester Hospital, Salford, UK. Ethical approval was granted from the Ethical Committee at the University of Nottingham (ATCS number 1559). A power calculation demonstrated that 50 animals were required (25 per group) for a 90% likelihood of showing a 10 mm increase in dynamic interactive visual analogue scale (DIVAS) score. The study was a prospective, randomised, blinded clinical trial.

Animals

Fifty-one entire female cats were recruited from the RSPCA Greater Manchester Animal Hospital. Of these, 33 were owned and 18 were unowned shelter animals undergoing assessment and preparation for rehoming. All owners provided informed consent for the cat to be included in the study. Cats were starved for 12 h prior to admission. Following admission, cats received a physical and behavioural assessment and were then left undisturbed in a heated kennel for 10 mins. A temperament score was given (0 = quiet, 1 = anxious, 2 = nervous, 3 = aggressive). Inclusion criteria were healthy female cats (American Society of Anesthesiologists [ASA] status I or II) with a body condition score <6/9. Systemically unwell cats were excluded, as were cats receiving analgesic drugs.

Premedication

Animals were randomly assigned to the medetomidine and buprenorphine group (MB group) or the medetomidine and methadone group (MM group) (www+.randomizer.org). Cats in the MB group received 600 μg/m² medetomidine and 180 μg/m² buprenorphine, and cats in the MM group received 500 μg/m² medetomidine and 5 mg/m² methadone via deep IM injection into the quadriceps muscle. Heart rate (HR) respiratory rate (RR), mucous membrane colour, capillary refill time (CRT), aural temperature and subjective strength of peripheral pulses were monitored prior to premedication and at 5 min intervals thereafter. Subcutaneous meloxicam was administered 3 mg/m² in the MB group and 2.5 mg/m² in the MM group. A single-blinded observer subjectively assessed sedation quality by assessing demeanour, muscle relaxation, palpebral response, responses to clapping, ocular lubricant application and subcutaneous meloxicam administration.

Anaesthesia

Fifteen minutes after the premedication, anaesthesia was induced by IM administration of 3 mg/kg alfaxalone (Alfaxan; Jurox) into the quadriceps muscle and any responses were recorded. In a shelter environment, IV access is rarely prioritised for routine procedures in healthy animals, given time pressures and the relatively low risk for the patient. Therefore, IV catheterisation was only carried out in pregnant and ASA status II animals. Five minutes later, the induction quality was assessed by subjective parameters, including palpebral response, level of jaw tone and response to prophylactic IM amoxicillin administration (administered into the quadriceps muscle in the opposite leg to the alfaxalone). The response to laryngeal application of lidocaine (Intubeaze; Dechra) and endotracheal intubation were recorded. Anaesthesia was maintained with isoflurane (Isoflo; Zoetis) in 100% oxygen delivered via an Ayre’s T piece (with Jackson-Rees Modification, closed tail bag and paediatric adjustable pressure-limiting valve) and adjusted as necessary during surgery. All cats were placed in dorsal recumbency on a heated table.

Intraoperative monitoring included HR, RR, mucous membrane colour, SpO₂% lingual probe (model VE-H100B; Eden Instruments), indirect measurement of systolic (SAP), mean (MAP) and diastolic (DAP) arterial blood pressures (MDPRO Cat and Dog Blood Pressure Monitor; MemoDiagnostic) and aural temperature (VT-150 Instant Animal Ear Thermometer; Vet-Temp). Observations were undertaken by an individual unaware of the treatment group.

Surgery

All cats underwent midline OVH by a single surgeon.

Recovery

Upon completion of surgery, isoflurane was discontinued and oxygen was supplied for 5 mins before extubation. Immediately after extubation, atipamezole was administered IM into the quadriceps muscle at 50% of the original volume of medetomidine. The animal was subsequently placed into a heated kennel.

Assessment of pain

Pain assessments by a blinded observer were carried out at 10, 20 and 30 mins after extubation. Four metrology scales were utilised at each of these time points. These included simple descriptive scale, numerical scale, DIVAS and the UNESP-Botucatu multidimensional scale.

Statistical analysis

Statistical analysis was carried out using GraphPad Prism 7 (GraphPad Software). Continuous data were assessed for normality using the D’Agostino and Pearson test. Parametric and non-parametric data were analysed using the Student’s t-test and Mann–Whitney U-test/two-sample Wilcoxon test, respectively. Normally distributed data are presented as mean ± SD and non-parametric data are presented as median (range). Statistical significance was set at P <0.05.

Results

Animals

Fifty-one female cats were recruited to this study over an 8 month period. All animals were ASA status I, except for one cat which had a grade II systolic heart murmur but was otherwise healthy and asymptomatic, classed as ASA status II. There were no significant differences in weight, age or temperament between groups (Table 1).

Table 1

Demographic data of the 41 female cats that completed the study

Parameter	Group
Parameter	MB (n = 21)	MM (n = 20)
Age (months)	12 (3–48)	14 (2–48)
Weight (kg)	2.4 ± 0.5	2.3 ± 1.0
Temperament score (0–3)	1 (1–3)	1.5 (1–3)

Fifty-one cats were recruited to the study, nine cats were unsuitable for rehoming and underwent euthanasia during anaesthesia, and one cat did not receive atipamezole at the correct time and was excluded. Data are presented as mean ± SD or median (range) as appropriate. There were no significant differences between groups

MB = medetomidine and buprenorphine; MM = medetomidine and methadone

Ten animals were withdrawn at various points of the study in view of their unsuitability for re-homing and subsequent euthanasia (four in the MB group, five in the MM group), or a failed administration of atipamezole (one the MM group). Forty-one (21 in the MB group, 20 in the MM group) underwent OVH and subsequent pain-scoring assessments.

Premedication

There was a mild decrease in body temperature, HR and RR post-sedation, but these remained within normal limits. There were no significant differences in these parameters or the quality of sedation between groups after premedication (Table 2).

Table 2

Changes in physiological parameters, scores for induction and intubation and timing of procedures in 41 cats undergoing ovariohysterectomy

Parameter		MB group (n = 21)	MM group (n = 20)
Baseline (prior to premedication)
Temperature (°C)		38.5 ± 0.8	38.4 ± 0.7
HR (beats/min)		166 ± 28	172 ± 24
RR (breaths/min)		54 ± 16	52 ± 15
Post-premedication
Temperature (°C)		38.0 ± 0.9	38.1 ± 0.8
HR (beats/min)		105 ± 29	105 ± 32
RR (breaths/min)		40 ± 11	40 ± 12
IM alfaxalone injection response	Score
No physical response	0	14	12
Any physical response, including leg twitches or movement	1	5	5
Not recorded		2	3
Post-induction of anaesthesia
Time from sedation to induction (mins) (range)		15–16	13–15
Temperature (°C)		37.8 ± 0.9	37.8 ± 0.7
HR (beats/min)		110 ± 28	121 ± 36
RR (breaths/min)		40 ± 9	40 ± 10
SAP (mm Hg)		136 ± 31	139 ± 30
MAP (mm Hg)		101± 21	105 ± 24
DAP (mm Hg)		84 ± 20	85 ± 19
Ease of intubation	Score
Very smooth: first attempt successful, no patient response	1	12	14
Smooth: some movement of jaw or tongue, mild coughing	2	6	3
Poor: swallowing, coughing and signs of distress	3	2	1
Very poor: unsuccessful intubation, signs of severe distress	4	1	0
Not recorded		0	2
Surgery
Surgery duration (mins)		24 ± 8	22 ± 8
Extubation
Temperature at time of extubation (°C)		35.8 ± 1.1	35.6 ± 0.9
HR at time of extubation (beats/min)		102 (72–128)	98 (76–186)
RR at time of extubation (breaths/min)		28 (12–48)	24 (20–64)

Cats either received medetomidine and buprenorphine (MB) or methadone and medetomidine (MM) prior to intramuscular (IM) induction of anaesthesia with alfaxalone. Data are presented as mean ± SD or median (range) as appropriate. There were no significant differences between groups

HR = heart rate; RR = respiratory rate; SAP = systolic arterial pressure; MAP = mean arterial pressure; DAP = diastolic arterial pressure

Induction

There were no significant differences between the quality of induction after alfaxalone administration. There were no significant differences in MAP, SAP, DAP, HR or RR between the groups after induction (Table 2). There were no significant differences in response to laryngeal spray between the MB and MM groups. Intubation scores were variable (Table 2) but were not found to be significantly different between the two groups.

Maintenance of anaesthesia and surgery

There were no obvious incidences of post-induction apnoea (PIA) measured by assessing RR, although general assessment of cardiopulmonary function was limited in this setting and for this population of healthy cats. Isoflurane vaporiser settings ranged between 0.5% and 1.5% and no significant difference was found between vaporiser settings or surgery time between the MB and MM groups. During surgery, there were no significant differences in mucous membrane colour, moisture or CRT, SAP, MAP, DAP, temperature, HR or RR between the two groups.

Recovery and pain assessment

Temperature, HR and RR were reduced from the initial reading to the readings during recovery but were not found to be different between the two groups (Table 3).

Table 3

Heart rate (HR), respiratory rate (RR) and aural temperature of 41 cats undergoing ovariohysterectomy during the first 30 mins of recovery

Parameter	MB (n = 21)			MM (n = 20)
	10 mins	20 mins	30 mins	10 mins	20 mins	30 mins
HR (beats/min)	144 ± 26	153 ± 24	158 ± 34	152 ± 30	156 ± 30	156 ± 33
RR (breaths/min)	30 ± 7	30 ± 9	30 ± 7	34 ± 7	36 ± 10	35 ± 7
Temperature (°C)	35.5 ± 0.7	35.7 ± 0.6	36.1 ± 0.7	35.3 ± 0.9	35.5 ± 1.1	36.1 ± 1.2

Cats either received medetomidine and buprenorphine (MB) or methadone and medetomidine (MM) prior to intramuscular induction of anaesthesia with alfaxalone. Data are mean ± SD. There were no significant differences between groups, or within groups at any time point

Of the four metrology scales utilised in this study at three time points, none indicated necessary administration of rescue analgesia (Table 4). At 10 mins the DIVAS pain score was significantly higher in the MB group compared with the MM group (P = 0.0272) (Figure 1).

Table 4

Scores of the three metrology instruments (numeric rating scale [NRS], simple descriptive scale [SDS], dynamic interactive visual analogue scale [DIVAS] and UNESP-Botucatu multidimensional pain scale [MFPS]) in 41 cats undergoing ovariohysterectomy

Pain scoring system	Time (mins)	MB (n = 21)	MM (n = 20)	P value
NRS (0–4)
	10	0 (0–2)	0 (0–2)	0.387
	20	0 (0–4)	0 (0–1)	0.416
	30	0 (0–2)	0 (0–0)	0.107
SDS (0–3)
	10	1 (1–3)	1 (1–2)	0.395
	20	1 (1–3)	1 (1–2)	0.311
	30	1 (0–2)	2 (0–1)	0.285
DIVAS (0–100 mm)
	10	2 (0–54)	1 (0–21)	0.027*
	20	2 (0–36)	2 (0–7)	0.474
	30	2 (0–20)	2 (1–6)	0.346
UNESP-Botucatu MFPS (0–30)
	10	1 (0–4)	1.5 (0–5)	0.66
	20	0 (0–5)	0.5 (0–4)	0.818
	30	1 (0–5)	0 (0–3)	0.524

Cats either received medetomidine and buprenorphine (MB, n = 21) or methadone and medetomidine (MM, n = 20) prior to intramuscular induction of anaesthesia with alfaxalone. Data are median (range)

P <0.05 between the two groups

Figure 1

Postoperative pain scores evaluated with a dynamic interactive visual analogue scale (DIVAS) at 10, 20 and 30 mins after extubation in 41 cats undergoing ovariohysterectomy after medetomidine and buprenorphine (MB) (n = 21) or methadone and medetomidine (MM) (n = 20) followed by intramuscular alfaxalone. *P <0.05 between the two groups

Discussion

IM combinations for feline anaesthesia are useful in private practice, as well as high-throughput shelters focusing on population control. Drug combinations often include alpha₂ (α₂)-adrenoreceptor agonists, opioids and ketamine.^20–22 However, alternatives for ketamine may be desirable given: (1) the uncertainty of its future availability; and (2) the increase in myocardial oxygen demand, leading to a higher risk in fractious/feral cats where examination may be unfeasible, particularly if there is underlying cardiac disease.^22,23

This study investigated IM protocols in cats undergoing OVH. Anaesthetic and analgesic qualities were compared between methadone and buprenorphine combined with medetomidine following induction of anaesthesia with IM alfaxalone.

In both groups, sedation was profound enough to fully examine the cats and induce anaesthesia smoothly. Post-sedation, HR, RR and temperature decreased slightly but remained within normal limits. Other subjective parameters such as palpebral response, and responses to ocular lubricant and subcutaneous meloxicam injection, also indicated a deep level of sedation in both groups. Slingsby et al and Grint et al also found superior sedation quality when combining opioids with medetomidine.^6,7 These results are expected given that opioids and α₂-adrenergic agonists work synergistically as a result of sharing post-receptor mechanisms of action.²⁴ A slightly lower dose of medetomidine and meloxicam were administered in the MM group, as methadone is a full mu-agonist and its sedative and analgesic effects were expected to be more profound than buprenorphine. This was based on extensive experience with the ‘Kitten Quad’ protocol, featuring the same doses of methadone, buprenorphine and medetomidine as this study.¹ The body surface area (BSA) of dosing and the simplicity of using equal volumes of the α₂ agonists and opioid drugs were chosen for the ‘Kitten Quad’ to improve potential uptake of the regime in clinical practice. The BSA dosing improves reliability in smaller patients and improves affordability in larger patients when compared with standard linear dosing.

Induction of anaesthesia with 3 mg/kg IM alfaxalone was well tolerated and allowed smooth intubation on the first attempt in the majority of patients, with a minority requiring a 45–60 s delay and one subsequent attempt. All cats could be intubated. Grubb et al described discomfort and severe reactions following 5 mg/kg alfaxalone IM, likely caused by volume, as IM administration of alfaxalone itself does not cause tissue irritation (Jurox technical notes).²⁵ In the current study, 70% of animals exhibited no reaction, with the remainder exhibiting a small leg twitch. One limitation of the IM route is that it cannot be given ‘to effect’, meaning that some animals may receive more drug than necessary. Post-induction, there were no incidences of PIA and minimal signs of cardiorespiratory depression. Other studies have also observed minimal depressive cardiorespiratory effects, with mixed reports regarding prevalence of PIA (IV route only).^{13,14,16,22,25–27} To our knowledge, PIA has not been reported with IM administration, possibly because this allows a more gradual delivery of the drug to the bloodstream.

As a common procedure resulting in moderate pain, OVH was the chosen surgical procedure for the study.^9,10 Intraoperatively, cardiovascular parameters remained stable and fractional inspired isoflurane concentration was lower than in similar studies.^13,16 Transient, mild-to-moderate hypotension (MAP <70 mmHg) occurred in both groups, similar to the findings of Zaki et al,¹⁴ which may have been caused by the combination of the isoflurane and alfaxalone. However a non-invasive blood pressure monitor was used, making accurate conclusions regarding this observation difficult.

Postoperatively, patients exhibited overall smooth and excitement-free recoveries. This may be due to the synergism between opioids and α₂-adrenergic agonists.²⁸ Assessments showed that 75% of cats exhibited a normal posture and 90% were eating within 30 mins. At 10 mins postoperatively, DIVAS pain scores were significantly higher in the MB group than in the MM group, but not high enough to prompt the administration of rescue analgesia. This could be owing to the full μ-agonist classification of methadone and therefore higher potency in the provision of analgesia.²⁹ There could also be a difference in time of onset of analgesia, which may differ between methadone and buprenorphine.⁴ At all other measured time points, there were no significant differences in pain scores or physiological parameters between the groups.

Multimodal analgesia was augmented with a subcutaneous meloxicam injection 5 mins after induction. This may have contributed to a lack of rescue analgesia being necessary in the recovery period, and while in some studies the non-steroidal anti-inflammatory drug (NSAID) is omitted for comparisons to be made, this study included a preoperative NSAID to represent the typical clinical scenario and because of the superior analgesia it offers.^24,30 Although some preclinical studies have suggested analgesic properties of alfaxalone, the clinical significance of this is unclear.^31–33

There were no adverse events in this diverse study population, inclusive of pre-pubertal and pregnant cats. Other studies have found alfaxalone suitable in young cats, although the drug was administered IV.^14,34

This practice-based study involved a number of limitations. IV catheters were not placed in healthy cats, posing a risk in rare cases of adverse drug reactions and difficult intubations. Each patient’s need for IV access should be assessed individually, and emergency equipment made readily available. More comprehensive intraoperative monitoring may have provided better understanding of the cardiovascular effects. During recovery, background disruption from the busy hospital and/or the nervous/aggressive nature of cats may have affected behavioural interpretations. However, this was also deemed representative of a realistic clinical setting.

Further study on the effectiveness of these protocols on truly ‘feral’ cats is recommended, as there were no feral cats in the current study population. The number suggested by the initial power calculation was not reached, owing to a number of omissions, including staff availability. A larger study population may have indicated significant differences at other time points. If recovery assessments were carried out for longer than 30 mins, further insights may have been gained into the duration of analgesia of each protocol, but may have also shown differences between the scoring tools used. It should be noted that although pain scores were only recorded up to 30 mins postoperatively, animals were continually and closely monitored beyond this time until discharge.

One validated scale for acute pain and three unvalidated scales were used in this study as this reflects to some extent some of the scales being used in different practice environments and evaluate differences with one observer.

Conclusions

Methadone and buprenorphine combined with medetomidine at the given doses provided safe and stable sedation in ASA status I cats, and subsequent IM alfaxalone provided a plane of anaesthesia suitable for carrying out invasive surgery perceived to cause moderate pain. Following this protocol, animals were found to recover smoothly, with no requirements for rescue analgesia. Multimodal analgesia is recommended, and, in this study, meloxicam was administered preoperatively.

Footnotes

Acknowledgements

The authors thank Albert Holgate for his contribution to the data collection.

Accepted: 2 January 2019

Author note

The preliminary data of this study were presented at the Association of Veterinary Anaesthetists Manchester Spring Meeting 2017.

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Alaleh Mahdmina

Kate L White

References

Joyce

Yates

Help stop teenage pregnancy! Early-age neutering in cats. J Feline Med Surg 2011; 13: 3–10.

The Cat Group. Policy statement 1: timing of neutering. http://www.thecatgroup.org.uk (accessed December 14, 2017).

Selmi

Mendes

Lins

, et al. Comparison of xylazine and medetomidine as premedicants for cats being anaesthetised with propofol-sevoflurane. Vet Rec 2005; 157: 139–143.

Robertson

Taylor

Lascelles

BDX

, et al. Changes in thermal threshold response in eight cats after administration of buprenorphine, butorphanol and morphine. Vet Rec 2003; 153: 462–465.

Bortolami

Murrell

Slingsby

LS.

Methadone in combination with acepromazine as premedication prior to neutering in the cat. Vet Anaesth Analg 2013; 40: 181–193.

Grint

Burford

Dugdale

AHA

. Investigating medetomidine-buprenorphine as preanaesthetic medication in cats. J Small Anim Pract 2009; 50: 73–81.

Slingsby

Bortolami

Murrell

JC.

Methadone in combination with medetomidine as premedication prior to ovariohysterectomy and castration in the cat. J Feline Med Surg 2015; 17: 864–872.

Hall

Duke

Townsend

, et al. The effect of opioid and acepromazine premedication on the anesthetic induction dose of propofol in cats. Can Vet J 1999; 40: 867–870.

Mathews

Kronen

Lascelles

, et al. Guidelines for recognition, assessment and treatment of pain. J Small Anim Pract 2014; 55: E10–E68. DOI: 10.1111/jsap.12200.

10.

Mathews

KA.

Pain assessment and general approach to management. Vet Clin North Am Small Anim Pract 2000; 30: 729–755.

11.

Jurox

Alfaxan

. Package insert, 2017.

12.

Warne

Beths

Whittem

, et al. A review of the pharmacology and clinical application of alfaxalone in cats. Vet J 2015; 203: 141–148.

13.

Taboada

Murison

PJ.

Induction of anaesthesia with alfaxalone or propofol before isoflurane maintenance in cats. Vet Rec 2010; 167: 85–89.

14.

Zaki

Ticehurst

Miyaki

Clinical evaluation of Alfaxan-CD as an intravenous anaesthetic in young cats. Aust Vet J 2009; 87: 82–87.

15.

Mathis

Pinelas

Brodbelt

, et al. Comparison of quality of recovery from anaesthesia in cats induced with propofol or alfaxalone. Vet Anaesth Analg 2012; 39: 282–290.

16.

Muir

Lerche

Wiese

, et al. The cardiorespiratory and anesthetic effects of clinical and supraclinical doses of alfaxalone in cats. Vet Anaesth Analg 2009; 36: 42–54.

17.

Khenissi

Nikolayenkova-Topie

Broussaud

, et al. Comparison of intramuscular alfaxalone and ketamine combined with dexmedetomidine and butorphanol for castration in cats. J Feline Med Surg 2017; 19: 791–797.

18.

Adami

Imboden

Giovannini

, et al. Combinations of dexmedetomidine and alfaxalone with butorphanol in cats: application of an innovative stepwise optimisation method to identify optimal clinical doses for intramuscular anaesthesia. J Feline Med Surg 2016; 18: 846–853.

19.

Rodrigo-Mocholí

Belda

Bosmans

, et al. Clinical efficacy and cardiorespiratory effects of intramuscular administration of alfaxalone alone or in combination with dexmedetomidine in cats. Vet Anaesth Analg 2016; 43: 291–300.

20.

Granholm

McKusick

Westerholm

, et al. Evaluation of the clinical efficacy and safety of dexmedetomidine or medetomidine in cats and their reversal with atipamezole. Vet Anaesth Analg 2006; 33: 214–223.

21.

Navarrete

Domínguez

del Mar Granados

, et al. Sedative effects of three doses of romifidine in comparison with medetomidine in cats. Vet Anaesth Analg 2011; 38: 178–185.

22.

Cremer

Riccó

CH.

Cardiovascular, respiratory and sedative effects of intramuscular alfaxalone, butorphanol and dexmedetomidine compared with ketamine, butorphanol and dexmedetomidine in healthy cats. J Feline Med Surg 2018; 20: 973–979.

23.

Clutton

ER.

Cardiovascular disease. In: Seymour

Duke-Novakovski

(eds). BSAVA manual of small animal anesthesia and analgesia. Gloucester: BSAVA, 2007, pp 200–219.

24.

Fernandez-Parra

Adami

Dresco

, et al. Dexmedetomidine-methadone-ketamine versus dexmedetomidine-methadone-alfaxalone for cats undergoing ovariectomy. Vet Anaesth Analg 2017; 44: 1332–1340.

25.

Grubb

Greene

Perez

TE.

Cardiovascular and respiratory effects, and quality of anesthesia produced by alfaxalone administered intramuscularly to cats sedated with dexmedetomidine and hydromorphone. J Feline Med Surg 2013; 15: 858–865.

26.

Beths

Touzot-Jourde

Musk

, et al. Clinical evaluation of alfaxalone to induce and maintain anaesthesia in cats undergoing neutering procedures. J Feline Med Surg 2014; 16: 609–615.

27.

Whittem

Pasloske

Heit

, et al. The pharmacokinetics and pharmacodynamics of alfaxalone in cats after single and multiple intravenous administration of Alfaxan at clinical and supraclinical doses. J Vet Pharmacol Ther 2008; 31: 571–579.

28.

Ossipov

Harris

Lloyd

, et al. Antinociceptive interaction between opioids and medetomidine: systemic additivity and spinal synergy. Anesthesiology 1990; 73: 1227–1235.

29.

Kerr

Pain management I: systemic analgesics. In: Seymour

Duke-Novakovski

(eds). BSAVA manual of canine and feline anaesthesia and analgesia. Gloucester: BSAVA, 2014, pp 89–103.

30.

Benito-de-la-Víbora

Lascelles

BDX

García-Fernández

, et al. Efficacy of tolfenamic acid and meloxicam in the control of postoperative pain following ovariohysterectomy in the cat. Vet Anaesth Analg 2008; 35: 501–510.

31.

Murison

Martinez Taboada

Taboada

FM.

Effect of propofol and alfaxalone on pain after ovariohysterectomy in cats. Vet Rec 2010; 166: 334–335.

32.

Pathirathna

Brimelow

Jagodic

, et al. New evidence that both T-type calcium channels and GABAA channels are responsible for the potent peripheral analgesic effects of 5α-reduced neuroactive steroids. Pain 2005; 114: 429–443.

33.

Jevtovic-Todorovic

Covey

Todorovic

SM.

Are neuroactive steroids promising therapeutic agents in the management of acute and chronic pain?

Psychoneuroendocrinology 2009; 34 Suppl 1: S178–S185.

34.

O’Hagan

Pasloske

McKinnon

, et al. Clinical evaluation of alfaxalone as an anaesthetic induction agent in cats less than 12 weeks of age. Aust Vet J 2012; 90: 395–401.