Imepitoin for noise aversion in dogs

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Imepitoin (a prescription-only POM-V medicine), which is authorised as an antiepileptic for dogs under the brand name Pexion, is now also authorised “for the reduction of anxiety and fear associated with noise phobia in dogs”. This module summarises what is known about the use of imepitoin in the management of noise phobia in dogs. By doing this module you will:

  • understand the mode of action of imepitoin in reducing fear and anxiety

  • be aware of the clinical evidence in support of this use

  • understand how imepitoin is used for treating noise phobia in dogs

  • know the adverse effects of imepitoin in dogs treated for noise phobia

  • know how to help clients use imepitoin safely and effectively.

In the UK, fireworks are the most commonly reported type of noise resulting in fear and anxiety in dogs. However, many other noises are also reported to cause significant problems including thunderstorms, gunshots and traffic noise. The signs of noise phobia have been reported to include restlessness, panting, vocalisation, cowering, trembling, frequent elimination, destructive behaviour, inappetence, owner-seeking behaviour and escape behaviours such as bolting. 

Treatment of noise phobia requires a good understanding of the fear response and, in each case, the predisposing, initiating and maintaining factors. Interventions include behavioural therapies such as environmental changes, owner education, desensitisation and counter-conditioning. Behavioural therapies may be supported by adjunctive therapies including dog-appeasing pheromone, nutritional supplements (e.g. alpha-casozepine), herbal remedies and drugs. The potential drug treatments include oral anxiolytics and antidepressants, such as alprazolam and propranolol (both unlicensed in dogs), and clomipramine, fluoxetine and selegiline (which are licensed for the treatment of behavioural disorders in dogs, but not specifically noise phobia). There are currently two drug treatments specifically authorised for use in dogs with fear an anxiety related to noise: one is dexmedetomidine oromucosal gel (brand name Sileo), and the other is imepitoin. This module focuses on imeptoin. A separate module will cover dexmedetomidine.

To understand how imepitoin works we first need to talk about GABA receptors in the brain, and a group of drugs called benzodiazepines. 

GABA (which is short for gamma-aminobutyric acid) is a chemical neurotransmitter in the brain. When GABA interacts with GABA receptors in the brain, a chemical change leads to nerve cells becoming inhibited or less excitable. Certain drugs can interact with GABA receptors. The most well known are the group of drugs called benzodiazepines (of which diazepam is a member). These bind to the GABA receptor causing several potentially useful effects, including reduced anxiety and sedation. Traditional benzodiazepines, such as diazepam, are called full agonists at the ‘benzodiazepine site’ of the GABA receptor. 

Imepitoin also binds to GABA receptors, but it binds more loosely than benzodiazepines. Imepitoin was originally developed with the aim of producing a drug like a benzodiazepine but with less sedation. In fact imepitoin produces about half the effects of diazepam. 

Imepitoin was originally authorised as an antiepileptic treatment in dogs. However, as well as having anti-seizure activity, experiments in rodents showed that imepitoin has anxiety-reducing effects, without causing sedation. 

The main clinical evidence supporting the licensed use of imepitoin in dogs with noise phobia is a single randomised, double-blinded, placebo-controlled trial. The trial included 238 client-owned dogs with owner-reported fear and anxiety to explosive noises. The dogs were randomised to receive a placebo or imepitoin at a dose of 30 mg/kg twice daily for 3 days starting 2 days before New Year’s Eve. In all, 65% of owners whose dogs received imepitoin reported a good or excellent overall treatment effect compared to 25% of those receiving placebo. Worsening of the condition was reported in 4% of dogs on imepitoin (vs. 5% for placebo), and there was no reported effect in 15% of dogs on imepitoin (vs. 49% for placebo). (CVMP 2018)

In clinical trials, adverse effects were reported in about half of the dogs taking imepitoin, although none were considered serious. 

  • Ataxia (loss of control of body movements) is the most common adverse effect of imepitoin (it was reported in 35% of dogs in the main clinical trial). It starts within a few hours of the first dose but resolves in most dogs within 48 hours while continuing treatment. Other adverse effects reported in dogs treated with imepitoin for noise phobia include: 

  • increased appetite and lethargy (in more than 1 in 10 dogs);

  • vomiting and aggression (in between 1 and 10 dogs in 100);

  • hyperactivity, sleepiness and hypersalivation (in between 1 and 10 dogs in 1,000).

Drugs that act at the benzodiazepine receptor site, including imepitoin, can lead to disinhibition of fear-based behaviours so they may result in a change in aggression levels in treated dogs. In the clinical trial of imepitoin described above, aggression was reported in three dogs (2.6%) on imepitoin.

As for all medications, it is important to report any adverse reactions to imepitoin seen in practice to the Veterinary Medicines Directorate (VMD) or the manufacturer.

The summary of product characteristics (SPC) states that imepitoin should not be used in dogs with severely impaired liver function and in severe renal or cardiovascular disorders. The use of imepitoin is not recommended in male breeding dogs, or in bitches during pregnancy or lactation.

Imepitoin has not been tested for reduction of fear and anxiety related to noise phobia in dogs aged under 12 months. Also, the safety of imepitoin has not been tested in dogs weighing under 2 kg or in dogs with renal, liver, cardiac, gastrointestinal or other disease.

No drug interactions have been reported with imepitoin. 

There is a small amount of evidence suggesting that imepitoin might help when used together with behavioural therapy in the treatment of dogs with fear- and anxiety-problems due to factors other than noise but this is an unauthorised use of the product.  

We do not know how imepitoin compares with other behavioural and drug treatments used in managing noise phobia.

Imepitoin is supplied as white, half-scored, oblong tablets which can be halved for appropriate dosing. The recommended dose of imepitoin is 30 mg/kg twice daily, given 12 hours apart. Food in the stomach reduces the absorption of imepitoin, so clients should be advised to keep the timing of doses in relation to food consistent. The treatment needs be started 2 days before the expected noise event and continued through the event. This is because the drug may be less effective in some dogs in the first day or so, and also because the adverse effects are most likely to occur soon after the start of treatment and to have resolved by the time of the noise event.

The main adverse effect is ataxia shortly after the first dose, but this resolves in most dogs by the end of day 2. It is important to warn clients that imepitoin may cause aggression in some dogs. 

Podcast

If you prefer, you can listen to the whole audio presentation of this module using the following podcast. Don't forget that you can also download the podcast to your iPod, music player, tablet or smartphone using the Download link on the right of the audio player.

Small dog with paws in his ears

How we produced this module

Our modules start with a detailed outline and electronic literature search. We then commission a collaborating author to draft the text of the module. The collaborating author on this module was Andrea Tarr and the editor was Kathryn Wareham. The draft is circulated unsigned to a wide range of commentators, including practising first-opinion vets, topic specialists, the companies that market any mentioned drugs and other organisations and individuals, as appropriate. They can raise points about the interpretation of evidence, ask questions that are important to clinical practice, and present alternative viewpoints. There is a rigorous editing and checking process and the result is a module that is evidence-based, impartial and relevant to clinical practice. The final module is unsigned because it is the result of collaboration.  

Literature search

We searched RCVS Knowledge Discovery Service (including PubMed) and VetMed Resource (CAB Abstracts), using the terms (imepitoin OR Pexion*) AND (dog OR dogs OR canine OR canines OR canis)

References

Blackwell EJ et al. (2013) Fear responses to noises in domestic dogs: prevalence, risk factors and co-occurrence with other fear related behaviour. Applied Animal Behaviour Science 145(1): 15

BSAVA Small Animal Formulary: Canine and Feline. 9th edition (2017) Ramsey I, editor.

Committee for Medicinal Products for Veterinary Use. CVMP assessment report for a grouped type II variation for Pexion, May 2018. Available: https://www.ema.europa.eu/documents/variation-report/pexion-v-c-2543-ii-0011-g-epar-assessment-report-variation_en.pdf. [Accessed 13.2.2019]

Engel O et al. (2018) Imepitoin shows benzodiazepine-like effects in models of anxiety. Frontiers in Pharmacology 9: 1225 

McPeake KJ & Mills DS. (2017) The use of imepitoin (Pexion) on fear and anxiety-related problems in dogs – a case series. BMC Veterinary Research 13:173

Mills D (2005) Management of noise fears and phobias in pets. In Practice 27: 248–55

Packer R et al. (2017) Investigating the potential of the antiepileptic drug imepitoin as a treatment for co-morbid anxiety in dogs with idiopathic epilepsy. BMC Veterinary Research 13: 90

PDSA and YouGov. PDSA Animal Wellbeing (PAW) Report (2011) The State of Our Pet Nation. Available from: https://www.pdsa.org.uk/media/2584/pdsa_animal_wellbeing_report_2011.pdf

Pexion 100mg, 400mg tablets. Summary of product characteristics. Boehringer Ingelheim Vetmedica GmbH, November 2017. https://www.ema.europa.eu/documents/product-information/pexion-epar-product-information_en.pdf. [Accessed 13.2.2019]

Plumb’s Veterinary Drugs monograph. https://www.plumbsveterinarydrugs.com/#!/search [Accessed 13.2.2019]

Rundfeldt C et al. (2014) Imepitoin as novel treatment option for canine idiopathic epilepsy: pharmacokinetics, distribution and metabolism in dogs. Journal of Veterinary Pharmacology and Therapeutics 37: 421–34

Rundfeldt C & Loscher W (2014) The pharmacology of imepitoin: the first partial benzodiazepine receptor agonist developed for the treatment of epilepsy. CNS Drugs 28: 29–43

Sherman BL & Mills DS (2008) Canine anxieties and phobias: an update on separation anxiety and noise aversion. Veterinary Clinics of North America: Small Animal Practice 38: 1081-106

Storengen LM & Lingaas F (2015) Noise sensitivity in 17 dog breeds: prevalence, breed risk and correlation with fear in other situations. Applied Animal Behaviour Science 171: 152-60

Waller, Sampson AP, Renwick AG et al, editors (2014). Medical pharmacology and therapeutics. Saunders Elsevier.

Imepitoin for idiopathic epilepsy in dogs.Veterinary Prescriber 2014; December.