Imepitoin for noise aversion in dogs
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Imepitoin, which is licensed as an antiepileptic for dogs under the brand name Pexion (Pexion SPC; Veterinary Prescriber 2014), is now also licensed “for the reduction of anxiety and fear associated with noise phobia in dogs” (Pexion SPC). In this module we examine the available evidence to find out how helpful imepitoin is in managing noise aversion 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 the new indication
understand how to use imepitoin for treating noise aversion in dogs
know the adverse effects of imepitoin in dogs treated for noise aversion.
The most commonly reported type of noise aversion in dogs in the UK is to fireworks (PDSA Paw Report 2011; Blackwell et al 2013). However, many other noises are also reported to cause significant problems including thunderstorms, gunshots and traffic noise (Sherman & Mills 2008; Storengen & Lingaas 2015). Symptoms of noise aversion have been reported to include restlessness, panting, vocalisation, cowering, trembling, frequent elimination, destructive behaviour, inappetence, owner-seeking behaviour and escape behaviours such as bolting (Mills 2005; Sherman & Mills 2008).
Treatment of noise aversion 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 (Mills 2005). 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 aversion) (Mills 2005). There are currently two drug treatments specifically licensed for treating noise aversion in dogs: dexmedetomidine oromucosal gel (brand name Sileo), which is licensed for “the alleviation of acute anxiety and fear associated with noise in dogs” (Sileo SPC), and imepitoin, which is licensed “for the reduction of anxiety and fear associated with noise phobia in dogs”.
Imepitoin is a low-affinity partial agonist at the ‘benzodiazepine site’ on the gamma-aminobutyric acid A (GABAA) receptor complex (Rundfeldt & Loscher 2014).
GABA is the primary inhibitory neurotransmitter in the central nervous system (CNS). Stimulation of GABA receptors by GABA increases influx of chloride into the neuron, leading to hyperpolarisation of the cell membrane and decreased cell excitability. There are two main types of GABA receptor: GABAA causes rapid inhibition and GABAB causes a slower and more prolonged response (Waller et al 2014). The GABAA receptor consists of several subunits, which exist in several forms; this is why the GABAA receptor is regarded as a family of receptors. Benzodiazepines act by binding to subunits of the GABAA receptor to induce a conformational change that enhances the affinity of the receptor complex for GABA, thus increasing inhibition (Waller et al 2014). The increase in inhibitor neurotransmission produced by benzodiazepines has several potentially useful effects, including reduced anxiety. Traditional benzodiazepines, such as diazepam, are full agonists at the ‘benzodiazepine site’. Partial agonists of the site, such as imepitoin (which produces about 40–50% of the GABA-receptor stimulation caused by diazepam), were originally developed with the aim of producing drugs like benzodiazepines but with less sedation, and less likelihood of tolerance and dependence (Rundfeldt & Loscher 2014).
In dogs imepitoin has an elimination half life of 1.5 to 2 hours; most of the drug and its metabolites are excreted in the faeces and the remainder in urine (Rundfeldt et al 2014).
Imepitoin was originally licensed as an antiepileptic in dogs. However, as well as having anti-seizure activity, in pre-clinical rodent experiments imepitoin has been shown to have anxiolytic effects, without causing sedation, (Rundfeldt & Loscher 2014; Engel et al 2018). During the development of imepitoin for the treatment of idiopathic epilepsy in dogs, it was reported anecdotally that some owners wanted to continue using imepitoin because of reported improvements in their dog’s behaviour, even when seizure frequency was unaffected (Packer et al 2017; Rundfeldt & Loscher 2014). However, in a study of 85 dogs with idiopathic epilepsy there was no reduction found in owner-rated fear- and anxiety-related behaviours when the dogs were being treated with imepitoin for seizures (rather than behavioural problems) compared to before (Packer et al 2017). It is worth noting that the dogs in this study had not been specifically diagnosed with behavioural problems.
The main clinical evidence supporting the licensed indication for imepitoin in dogs with noise aversion is a single randomised, double-blinded, placebo-controlled, multi-site trial (conducted across Germany and the Netherlands). It has not yet been published but is described in the European Public Assessment Report (EPAR – which outlines the licensing decision (CVMP 2018). The trial (which is described in the report as well-conducted) included 238 client-owned dogs with owner-reported fear and anxiety to explosive noises shown consistently in the home and in the owner’s presence, and a Lincoln Sound-Sensitivity Scale (LSSS) score above 30 (CVMP 2018). The dogs were randomised to receive a placebo (124 dogs) or imepitoin at a median oral dose of 30 mg/kg twice daily for 3 days (114 dogs) starting 2 days before New Year’s Eve. There were two reported primary outcome measures: owner-assessed overall effect (as compared to the previous years without treatment) and the mean difference in behaviour score between the two groups. Both outcomes have been shown to be valid measures of the effect of drugs on anxiety (CVMP 2018).
In the results, 226 dogs were included in the full analysis set. More owners whose dogs received imepitoin reported a good or excellent overall treatment effect compared to those receiving placebo (64% vs. 25%; p<0.05). 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, no p value given). The mean anxiety score was around 12 for dogs on imepitoin, versus 18 with placebo, which the EPAR states is a clinically significant difference.
The European assessors considered imepitoin to have a positive benefit-risk balance and approved the new indication. However, they altered the proposed wording of the indication from “for the control of fear and anxiety associated with noise phobia in dogs” to “for the reduction of fear and anxiety associated with noise phobia in dogs” (CVMP 2018).
There are details missing from the description of this clinical trial, which make independently assessing its quality, reliability and risk of bias challenging. For example, the method of randomisation is not described, the statistical methods are not described in full (no level of statistical significance is stated in the methods), there is no full description of blinding within the study and no sample size calculation or power calculation provided to support the group sizes that were used. One of the primary outcomes was based on the owners’ recall of events from the previous year without treatment, compared to the current year with treatment, which is subjective and could be affected by recall bias. It is also possible that the high likelihood of the dogs on imepitoin showing ataxia as an adverse effect (see below) might have affected blinding and potentially exaggerated the perceived effects of imepitoin: owners may have guessed that their dog was on imepitoin and therefore expected to see an improvement.
In addition to the information from the clinical trial, a case-series looking at the use of imepitoin for treating fear- and anxiety-related problems in 19 dogs alongside behavioural therapies has been published (McPeake & Mills 2017). Dogs in the study were started on 10 mg/kg of imepitoin twice daily and then the dose adjusted throughout the study (11 — 19 weeks long) as required for the individual. Owner diaries and phone call discussions were used to create ‘average weekly fear anxiety reaction’ scores and ‘average weekly global fear anxiety scores’. For the 14 dogs in the study that suffered with noise sensitivity, there was a statistically significant improvement in the average weekly reaction scores across the study (p=0.003). Case reports are a lower level of evidence than randomised controlled trials and so this information offers weak support for the results of the clinical trial.
In the randomised controlled trial described in the imepitoin noise aversion licensing documents, adverse effects were significantly more common with imepitoin (occurring in 48% of dogs vs. 11% with placebo), although none were considered serious. Ataxia was most common (35% vs. 2%) starting within a few hours of the first dose but resolving in 76% of dogs within 48 hours while continuing treatment. In 11 dogs, ataxia resulted in treatment being withdrawn or in a dose reduction. 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) (Pexion SPC).
Drugs that act at the benzodiazepine receptor site, including imepitoin, can lead to disinhibition of fear-based behaviours so may result in a change in aggression levels. In the clinical trial described above, aggression was reported in three dogs (2.6%) on imepitoin (CVMP 2018; Pexion SPC).
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.
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 (Pexion SPC). This is at the top of the dose range recommended for the treatment of epilepsy (10 to 30 mg/kg twice daily). Food in the stomach reduces the absorption of imepitoin, so timing of dosing in relation to food should be consistent (Pexion SPC). Treatment should be started 2 days before the expected noise event and continued through the event (Pexion SPC). The rationale for this is that the drug may have a sub-optimal effect in some dogs earlier than 2 days, and because many of the adverse effects occur soon after the start of treatment and will have resolved by the time of the noise event (CVMP 2018). Longer durations of treatment for noise phobia should be based on benefit-risk assessments made by the vet (Pexion SPC).
The summary of product characteristics (SPC) contraindicates the use of imepitoin in dogs with severely impaired liver function and in severe renal or cardiovascular disorders (Pexion SPC). The use of imepitoin is not recommended in male breeding dogs, or in bitches during pregnancy or lactation (Pexion SPC).
Particular care is needed to weigh up the risk-benefit ratio in dogs with a history of aggression; the SPC suggests considering behaviour therapy before starting treatment with imepitoin in such dogs (Pexion SPC).
Imepitoin has not been tested for reduction of fear and anxiety related to noise aversion 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 (Pexion SPC).
No drug interactions have been reported with imepitoin (Pexion SPC). The effects of imepitoin might be expected to be reversed by flumazenil, a benzodiazepine antagonist (Plumb’s 2018).
The British Small Animal Veterinary Association (BSAVA) Small Animal Formulary states that “imepitoin may also be used in combination with a behaviour modification plan for the control of anxiety in dogs in relation to both social stimuli (e.g. crowds, strangers) and non-social stimuli (e.g. noises, novel items, new environments), once any role of pain has been controlled.” (BSAVA 2017). Limited evidence to support these broader uses comes from the published case series described earlier, in which imepitoin was used as an adjunct to behavioural therapy, which also included dogs with non-social (other than noise-related) and social fear- and anxiety-problems (McPeake & Mills 2017). A statistically significant improvement in the average weekly reaction scores was also seen in the dogs with non-social and social fear and anxiety.
We found no published evidence looking at how imepitoin compares with other behavioural and drug treatments used in managing noise aversion.
Imepitoin, which has been available as a treatment for dogs with idiopathic epilepsy, is now also licensed for reducing fear and anxiety in dogs with noise phobia. In one randomised controlled trial, 65% of owners considered it had a good or excellent effect in reducing fear and anxiety caused by New Year’s Eve fireworks. The main adverse effect is ataxia shortly after the first dose, but this resolves in most dogs by the end of day 2. Clients should be warned that imepitoin may cause aggression in some dogs. Drug treatment is not a substitute for behavioural management.
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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.
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)
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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]
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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
Sileo 0.1mg/mL oromucosal gel for dogs. Summary of product characteristics. Orion Corporation, June 2015. Available: https://www.ema.europa.eu/documents/product-information/sileo-epar-product-information_en.pdf. [Accessed 13.2.19]
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Waller, Sampson AP, Renwick AG et al, editors (2014). Medical pharmacology and therapeutics. Saunders Elsevier.