Fireworks: can alpha-casozepine help?

 

Why do this module?

Noise aversion is common in pets. Management of noise aversion usually involves a combination of interventions, including behaviour therapy, pheromones, drugs and nutritional supplements. Alpha-casozepine (Zylkène capules) is one such supplement. This module looks at whether there is any evidence that alpha-casozepine is effective in helping cats and dogs with noise aversion.

 

The responses involved in an animal’s reaction to fear are complex, involving the autonomic nervous system and the neuroendocrine system, with the noradrenergic, serotonergic, dopaminergic and gamma amino butyric acid (GABA) pathways all playing a role. The signs of noise aversion relate to these physiological responses to stress. In dogs, they include trembling, shaking, salivating, hiding, panting, pacing, restlessness, inappropriate elimination, soliciting human attention, escaping confinement, destruction and barking (Blackwell et al 2013). The intensity of anxiety depends on the level of arousal and the nature of the anticipated danger. Cats are more likely to hide and exhibit freezing responses, which might explain why the behavioural effect of noise fear is relatively unreported in cats compared to dogs.

Fear of fireworks is the most commonly reported type of noise aversion in dogs in the UK; others are thunderstorms, gunshots and traffic noise (Sherman & Mills 2008; Storegen & Lingaas 2015). The extent of the problem is unclear, due in part to the difficulty of investigating the signs of fear and behavioural problems in animals based on the subjective assessment of owners. In one study of 383 dog owners, 49% recognised signs of fear relating to noise (Blackwell et al 2013). In another, involving 13,000 dog owners, 39% of dogs were reported to be afraid of fireworks, 26% loud noises and 25% thunder (PDSA 2015).

The causes of noise aversion may vary between individuals. Proposed mechanisms include: lack of habituation through early relevant socialisation; traumatic experience associated with noise exposure; stress-induced dishabituation (from other unrelated stressors); and social transmission (learned behaviour from another dog) (Iimura 2006). Factors associated with increased risk of noise sensitivity include the breed of dog, neutering and older age. The origin of a pet may also be a factor: in one study, noise fear was less likely in dogs belonging to owners who had bred them (Storegen & Lingaas 2015; Blackwell et al 2013).

If owners don't recognise signs of fear, they won't seek help. So providing owners with information about noise fear can help them recognise the typical signs, and prompt them to seek veterinary help.  

Treatment of noise fear should be multimodal. It requires a good understanding of the fear response and, in each case, the predisposing, initiating and maintaining factors. Interventions include behaviour therapy such as environmental changes, owner education, desensitisation and counter-conditioning. Behaviour therapy may be supported by pheromone products, drugs (including anxiolytics and antidepressants), nutritional supplements (such as alpha-casozepine) and herbal remedies. However, measuring the success of specific interventions is difficult due to the multi-factorial aspects of behaviour. For example, owner influence may be significant because owners tend to reinforce their dog seeking them out by rewarding them with vocal, eye or physical contact (Levine & Mills 2008).

Alpha-casozepine is a decapeptide derived from a naturally-occurring milk protein (bovine milk alpha (s1)-casein. It is categorised as a nutritional supplement and not licensed as a medicine in the UK. Alpha-casozepine is the ingredient in Zylkène, which is promoted as a natural product “that can help support dogs and cats in situations where they find they need to adapt their behaviour to cope” (www.zylkenepet.co.uk). Zylkène is available as capsules containing 75mg, 225mg or 450mg of alpha-casozepine. The contents of the capsules are administered by mixing with food. The company (Vetoquinol) recommends a daily dose of one or two capsules (equivalent to 15–30mg/kg) begun a few days before the expected start of noisy events. (www.zylkenepet.co.uk).

The rationale for using alpha-casozepine is based on the traditional belief that cows’ milk has tranquillising and sleep-inducing properties (Miclo et al 2001). However, the mode of action of alpha-casozepine is unclear. It is not clear whether alpha-casozepine is absorbed undigested or whether the action of digestive enzymes produces a bioactive fragment of the peptide (Cakir-Kiefer et al 2011). In-vitro experiments suggest the active component interacts with the benzodiazepine site of GABA type A receptors, although with less affinity than the benzodiazepine diazepam (Miclo et al 2001); it may compete with benzodiazepines for the receptor (Cakir-Kiefer et al 2011). Alpha-casozepine does not bind to peripheral benzodiazepine receptors and so is not thought to cause adverse effects typically associated with benzodiazepines, such as muscle weakness and ataxia (Miclo et al 2001). 

The complex pathways and relationships between the mechanisms involved in fear and noise aversion, owner behaviour and the subjective nature of owner monitoring make the design of randomised controlled trials challenging. We found two published randomised controlled trials of alpha-casozepine in cats and dogs, neither of which specifically studied effects on noise aversion.

One was a double-blind randomised placebo-controlled trial that evaluated the effect of alpha-casozepine (15mg/kg) or placebo, daily for 56 days in 34 cats (Beata et al 2007a). There was an improvement in the signs of fear and anxiety in socially stressful conditions in the cats on alpha-casozepine. However, the clinical significance of the changes are uncertain, and the small sample size and other methodological problems including uncertainty about the validity of the diagnostic tool, make it difficult to draw firm conclusions from the study.

The other was a study by the same authors, which evaluated alpha-casozepine in dogs (Beata et al 2007b). This trial compared alpha-casozepine (15mg/kg daily) to selegiline (0.5mg/kg) over 56 days. (Selegiline is a mono-amine-oxidase-B inhibitor licensed in the UK as Selgian tablets for the treatment of behavioural disorders associated with depression and anxiety in dogs. [Selgian SPC]) The trial involved 38 dogs with an anxiety disorder for 4 weeks. The dogs also had to have scored above 19 on the ‘emotional disorder in dogs’ (EDED*) scale. There was a statistically significant reduction in anxiety scores in both groups, and no significant difference between the groups, which lead the paper’s authors to conclude that the two interventions were equally effective. However, the authors noted that it was not possible to define either intervention as a success or failure until day 42 of the trial. It is not clear if the improvements were clinically significant and problems with the trial design (including small sample and no power calculation) mean it is not possible draw a firm conclusion about the efficacy of alpha-casozepine in dogs.

*The EDED scale ranges from 9 to 45 points, with normal dogs scoring 9 to 13; phobic dogs score between 14 and 18, and dogs with other anxiety-related disorders score between 18 and 30 (Beata 2007b),

There is published evidence suggesting the efficacy of alpha-casozepine in other species. Studies in rats showed alpha-casozepine reduces anxiety and improves sleep (Guesdon 2006). In a randomised placebo-controlled trial in 10 horses subjected to mildly aversive routine health procedures, alpha-casozepine supplementation was associated with a modest improvement in compliance and apparent comfort. (McDonnell et al 2014) In another involving six semi-feral ponies, alpha-casozepine appeared to have a calming effect (McDonnell et al 2013). In a double-blind randomised trial in 42 healthy humans, alpha-casozepine reduced biological indicators during stress tests (Messaoudi et al 2005).

There are no reported adverse effects to alpha-casozepine. (Miclo et al 2001) However, as it is a nutritional supplement there is no systematic study or reporting of adverse effects or interactions. It seems sensible to avoid using alpha-casozepine in patients being treated with drugs that act on GABA receptors because of the potential for interaction; such drugs include the anticonvulsants phenobarbital and imepitoin, and anxiolytics such as diazepam and alprazolam.

The typical daily cost is around 40p to 80p for a cat and around £1.40 to £3.40 for a dog, depending on size.

There is a plausible rationale for using alpha-casozepine, a substance derived from milk protein, to reduce anxiety. However, the clinical trial evidence in cats and dogs is weak and so we do not know how effective alpha-casozepine is in helping them cope with frightening noises. It is unlikely to be effective on its own in the case of strong aversions. There are no reported adverse effects to alpha-casozepine, but there may be a potential for interaction with some antiepileptic or anxiolytic drugs.

As a ‘natural product’, clients may wish to try it in preference to drug treatment. If used, alpha-casozepine should be viewed as an adjunct, rather than an alternative, to appropriate treatment. The most important factor for successful long-term management of noise aversion is an effective behavioural modification programme. As owners may not recognise signs of fear, providing information about noise fear can help them recognise the typical signs, and prompt them to seek veterinary help.  

Goal of activity: Update knowledge; help clinical decision-making

Authors/disclosures: Veterinary Prescriber editorial team/no conflict of interest

Specific learning objectives: to improve knowledge and understanding of alpha-casozepine 

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References

Beata C et al. Effect of alpha-casozepine (Zylkene) on anxiety in cats. J Vet Behav Clin Appl Res 2007; 2: 40–6.  

Beata C et al. Effects of alpha-casozepine (Zylkene) versus selegiline hydrochloride (Selgian, Anipryl) on anxiety disorders in dogs J Vet Behav Clin Appl Res 2007; 2: 175–83.

Blackwell EJ et al. Fear responses to noises in domestic dogs: prevalence, risk factors and co-occurrence with other fear related behaviour. Appl Anim Behav Sci 2013; 145: 15–25.

Cakir-Kiefer C et al. In vitro digestibility of alpha-casozepine, a benzodiazepine-like peptide from bovine casein, and biological activity of its main proteolytic fragments’. J Ag Food Chem 2011; 59: 4464–72.

Guesdon B et al. A tryptic hydrolysate from bovine milk αS1-casein improves sleep in rats subjected to chronic mild stress. Peptides 2006; 27: 1476–82.

Iimura K. The nature of noise fear in domestic dogs. Masters thesis, 2006. University of Lincoln

Levine ED, Mills DS. Long term follow up of the efficacy of a behavior treatment program for dogs with firework fears. Vet Rec 2008; 162: 657–9.

McDonnell SM et al. Modestly improved compliance and apparent comfort of horses with aversions to mildly aversive routine health care procedures following short-term alpha-casozepine supplementation. J Equine Vet Sci 2014; 34: 1016–20.

McDonnell SM et al. Calming benefit of short-term alpha-casozepine supplementation during acclimation to domestic environment and basic ground training of adult semi-feral ponies. J Equine Vet Sci 2013; 33: 101–6.

Messaoudi M et al. Effects of a tryptic hydrolysate from bovine milk αS1-casein on hemodynamic responses in healthy human volunteers facing successive mental and physical stress situations. Eur J Nutr 2005; 44: 128–32.

Miclo L et al. Characterization of α-casozepine, a tryptic peptide from bovine αs1-casein with benzodiazepine-like activity. FASEB J 2001; 15: 1780–2.

The People’s Dispensary for Sick Animals. PDSA Animal Wellbeing (PAW) Report, 2015.

Selgian. Summary of product characteristics. Ceva Sante Animale, September 2007.

Sherman BL, Mills DS. Canine anxieties and phobias: an update on separation anxiety and noise aversion. Vet Clin North America: Small Anim Pract 2008; 38: 1081-106.

Storengen LM, Lingaas F. Noise sensitivity in 17 dog breeds: prevalence, breed risk and correlation with fear in other situations. Appl Anim Behav Sci 2015; 171: 152-60.