Alfaxalone: one more arrow in our arrow quiver

Authors

  • Tilemahos Anagnostou DVM, PhD, DipECVAA - Companion Animal Clinic, School of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece

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In this edition of the Hellenic Journal of Companion Animal Medicine a systematic review of the literature by Zioga et al. (2021) has been published, regarding the intravenous administration of alfaxalone for induction or induction and maintenance of anaesthesia in dogs. Prior to reporting the interesting results of this article, a brief historical background concerning the clinical application of alfaxalone in companion animal veterinary medicine is essential.

Alfaxalone is a steroid general anaesthetic derived from progesterone. It was commercially available for the first time in the 1970’s in combination with another steroid anaesthetic, alfadolone. Alfaxalone is a more potent anaesthetic than alfadolone, however alfadolone has analgesic properties, as opposed to alfaxalone (Winter et al. 2003). These drugs are not water-soluble, therefore 20% “Cremophor EL” (castor oil) was used in the formulation of solutions. The inclusion of this “carrier” in these drugs however resulted in the manifestation of severe undesirable side-effects in some cases. In dogs, salivation, foot pad and palpebral oedema, hypotension and pulmonary oedema were observed due to the release of histamine, whereas “anaphylactoid reaction” could be potentially lethal. In cats there have been reports of subcutaneous oedema and oedema of the pinna, laryngospasm, hypotension and pulmonary oedema. Due to these undesirable side-effects, the commercial formulation of alfaxalone/alfadolone (Saffan®) was eventually withdrawn after about 20 years of availability.

In 2001, initially in Australia, a new formulation of alfaxalone (Alfaxan®) became commercially available for use in companion animal veterinary medicine, for the induction and maintenance of anaesthesia. A few years later, this formulation was approved and became available in Europe, and then in Canada and the USA. In this formulation, alfaxalone is not combined with another anaesthetic, however a possibly even more important difference from the older formulation is the fact that in order to formulate solutions of the drug castor oil is no longer used, but a new technology, that of cyclodextrins, which does not provoke the release of histamine therefore this formulation does not result in the usual undesirable side-effects. Cyclodextrins are ring chains of molecules of carbohydrates, arranged in a way that the hydrophilic segments are outside and the lipophilic segments are inside the ring. They are water-soluble, however in their hydrophobic centre they provide room for interaction with hydrophobic molecules, such as steroids (Brewster et al. 1989).

Another interesting point regarding the new formulation technology is that its pH is 6.5-7, therefore pain is not induced during intramuscular injection, as opposed to ketamine solutions (pH 3.5-5.5) which can result in pain during intramuscular injection. Regarding the intramuscular injection of alfaxalone however, it should be mentioned that in order to administer clinically effective intramuscular doses of alfaxalone, large volumes of the drug are necessary which is impractical to administer intramuscularly. The manufacturer has provided for commercial use alfaxalone in multiple dose vials that contain preservatives and can be used for 28 days (Alfaxan® Multidose summary of product characteristics 2020).

Alfaxalone induces general anaesthesia by acting on the GABAA receptors. The onset of action is rapid after intravenous administration and anaesthesia is accompanied by sufficient muscle relaxation. It is considered to be a safe drug with a wide therapeutic index [mean lethal dose (LD) to mean effective dose (ED) ratio: LD50/ED50]. An advantage of alfaxalone is that it can be administered intramuscularly. The induction of anaesthesia is usually smooth; however the administration of premedication is indicated (a2-agonists, opioids, phenothiazines etc.) prior to induction with alfaxalone. Alfaxalone can be administered as a constant rate infusion (CRI) for maintenance of anaesthesia. During the recovery period, there may be vocalisation, paddling, increased muscle tone etc., especially if no premedication has been used. This drug has no analgesic properties, therefore for painful procedures preemptive, multimodal analgesia both perioperative and postoperative have to be administered by other means.

Alfaxalone can result in respiratory system depression. Especially after rapid intravenous administration, apnoea often occurs. Therefore, pre-oxygenation and the administration of increased fraction of inspired oxygen are recommended during anaesthesia, as well as ensuring a patent airway for mechanical ventilation. Regarding the effects of alfaxalone on the cardiovascular system, at induction of anaesthesia an increase of heart rate and decrease of arterial blood pressure often occur, however hypertension may also be seen. It has been proposed that alfaxalone may be an anaesthetic with less marked action than other drugs on cardiovascular system baroreceptor function (Liao 2016). It is obvious that the effects of alfaxalone on the respiratory and cardiovascular systems are very similar to those of propofol.

Except of the intramuscular injection, which is a significant advantage especially in fractious cats, another major advantage of alfaxalone use in cats is that after constant rate infusion, prolonged recovery is not observed, in contrast with propofol. The cause of prolonged recovery observed in cats after constant rate infusion of propofol has been associated with insufficient glucuronidation of propofol in this animal species (Warne et al. 2015). On the contrary, alfaxalone appears to be less dependent on the metabolic pathway of glucuronidation in order to be metabolised, resulting in faster metabolism in cats. It has been reported that the hepatic extraction ratio of propofol in cats is 8.6 ml/kg/min, whereas that value for alfaxalone equals 25.1 ml/kg/min (Whittem et al. 2008).

Regarding the use of alfaxalone in female dogs undergoing caesarean section, studies have shown that the Apgar score was low for puppies (lower viability) when the bitch underwent total intravenous anaesthesia (TIVA) with alfaxalone compared to maintenance of anaesthesia with isoflurane (Conde Ruiz et al. 2016), however it was high (increased viability) when anaesthesia was induced with alfaxalone compared to propofol, followed by maintenance with isoflurane in both animal groups (Doebeli et al. 2013). In this study, the authors concluded that although puppy survival was similar after the administration of either of these drugs (alfaxalone or propofol), it was alfaxalone that was more frequently associated with improved viability of the neonates during the first 60 minutes after exiting the uterus.

Regarding the systematic review of the literature by Zioga et al. 2021 evaluating the intravenous administration of alfaxalone in dogs for induction or induction and maintenance of anaesthesia, the authors conclude that from the literature it can be concluded that the slow infusion of alfaxalone can reduce the incidence of apnoea and also the total required dose. In addition, they have noted that the main effects of the drug on the cardiovascular function are increased heart rate and small decrease in arterial blood pressure, whereas the effect on the respiratory function is respiratory acidosis. They have found that alfaxalone can be safely used in clinical practice and slow infusions can prevent apnoea, however they recon that its administration must be combined with simultaneous administration of appropriate analgesic drugs in painful surgical procedures.

Unfortunately, at the end of the chapter “Introduction” of the respective paper published in the present issue of the Hellenic Journal of Companion Animal Medicine it is written: “This drug is not currently available in Greece”. Until recently, drugs such as tramadol and buprenorphine were also not commercially available for veterinary use. It was relatively recently however that formulations for both of these analgesics became available for use in animals. The practitioners’ response was, in the opinion of the author, very positive and these drugs became available for use by veterinary practitioners as effective tools in pain management in animals, both in postoperative pain as well as other types of pain.

Alfaxalone can also become a very useful addition to the toolbox of the veterinary practitioner, as a drug for the peri-anaesthetic period. This anaesthetic drug has been used for many years in companion animals in European countries, but also in other countries such as the USA, Canada and Australia, with excellent results. Much like propofol -without replacing it– it can also find its place in the induction and/or maintenance of anaesthesia in companion animal medicine. The acceptance of the drug by the veterinary community of our country will also be very positive and warm. In particular its use for intramuscular injection in fractious cats will offer the opportunity to veterinary practitioners for a very good alternative to anaesthesia of these animals, which otherwise could not be subject for a thorough clinical or other pre-anaesthetic evaluation and might also suffer from subclinical hypertrophic cardiomyopathy. The only alternative anaesthetic that could be administered via intramuscular injection would be ketamine, which is known to be contraindicated in cases of hypertrophic cardiomyopathy.

Alfaxalone can become one more weapon in the quiver of the Greek veterinary practitioner which will add to the optimal perioperative management of cases they are called to manage.

References

Brewster ME, Estes KS, Bodor N (1989). Development of a non-surfactant formulation of alfaxalone through the use of chemically-modified cyclodextrines. J Parenter Sci Technol 43, 262-265.

Conde Ruiz C, Del Carro AP, Rosset E et al. (2016). Alfaxalone for total intravenous anaesthesia in bitches undergoing elective caesarean section and its effects on puppies: a randomized clinical trial. Vet Anaesth Analg 43, 281–290.

Doebeli A, Michel E, Bettschart R et al. (2013). Apgar score after induction of anesthesia for canine cesarean section with alfaxalone versus propofol. Theriogenology 80, 850–854.

Jurox Ltd (2020). Alfaxan® Multidose summary of product characteristics. http://www.alfaxan.co.uk/images/Alfaxan-Multidose-UK-2020.-Dog-cat-pet-rabbit.pdf

Liao P (2016). Anesthetic and Cardio-pulmonary Effects of Propofol or Alfaxalone with or without Midazolam Co-Induction in Fentanyl Sedated Dogs. PhD Thesis, University of Guelph, Ontario, Canada.

Warne LN, Beths T, Whittem T et al.. A review of the pharmacology and clinical application of alfaxalone in cats. Vet J 203, 141–148.

Whittem Τ, Pasloske KS, Heit MC et al. (2008). The pharmacokinetics and pharmacodynamics of alfaxalone in cats after single and multiple intravenous administration of Alfaxan® at clinical and supraclinical doses. J Vet Pharm Ther 31, 571–579.

Winter L, Nadeson R, Tucker AP et al. (2003). Antinociceptive properties of neurosteroids: A comparison of alfadolone and alfaxolone in potentiation of opioid antinociception. Anesth Analg 97, 798-805.

Zioga et al. (2021). A systematic review of the cardiopulmonary effects of alfaxalone when used as a main agent for induction and/or maintenance of anaesthesia in dogs. Hellenic J Comp Anim Med 22;80-95.

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Published

2022-03-02

How to Cite

Αναγνώστου Τ. (2022) “Alfaxalone: one more arrow in our arrow quiver”, Hellenic Journal of Companion Animal Medicine, 10(2), pp. 75–79. Available at: https://hjcam.hcavs.gr/index.php/hjcam/article/view/121 (Accessed: 18August2022).

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Editorials