Investigating the potential of the anti-epileptic drug imepitoin as a treatment for co-morbid anxiety in dogs with idiopathic epilepsy

Abstract

BackgroundBehavioural changes associated with idiopathic epilepsy (IE) have been identified in dogs, with fear and anxiety-related problems seen in both drug-naïve dogs and dogs treated with anti-epileptic drugs (AEDs). Treating anxiety-related behaviour in dogs with IE may be challenging, as seizures are a contraindication for many conventional anxiolytic drugs. In addition, many dogs with IE are already treated with AEDs to reduce their seizure frequency, which may have negative effects if used in polytherapy. Imepitoin is low-affinity partial agonist at the benzodiazepine (BDZ) site of the GABAA receptor, and has been demonstrated to have both anticonvulsant and anxiolytic effects in laboratory rodents. Imepitoin has been developed for the treatment of IE in dogs, with demonstrated anticonvulsant effects and high tolerability and safety. To date, imepitoin’s potential to reduce anxiety in dogs with IE has not been investigated. An online survey was conducted to investigate the effect of imepitoin on fear and anxiety-related behaviours in dogs with IE. Eighty-five valid responses were received from owners of dogs with IE currently treated with imepitoin. Anxiety-related behaviour was quantified before and during imepitoin treatment using a validated questionnaire tool (C-BARQ).ResultsNo differences were observed in the five fear/anxiety-related measures between the two time periods (before vs. during treatment) for dog directed fear, stranger directed fear, non-social fear, pain sensitivity and separation related behaviour. A median 45% reduction in seizure frequency/month was observed following imepitoin treatment; however, imepitoin did not appear effective in reducing seizure frequency in a minority of cases. Polyphagia was the most common chronic side effect, and more side effects were reported in polytherapy cases.ConclusionsImepitoin does not appear to improve anxiety-related behaviour in dogs with IE treated with this medication for its anti-epileptic effects. Investigating the effects of imepitoin upon the behaviour of dogs with recognised behavioural anxiety-related problems (e.g. specific fears and phobias, separation related behaviours), in both healthy dogs and dogs with epilepsy is required to further explore any potential anxiolytic effects of this medication.

Impact of canine epilepsy on judgement and attention biases

“…The majority of dogs with IE (22/33) were treated with ASDs, with twelve receiving polytherapy (two or more ASDs). Imepitoin has been found to have anxiolytic as well as antiseizure effects in physically healthy dogs 67 – 69 ; however, no changes in anxiety levels were reported by owners of dogs treated with imepitoin for IE 70 . In addition, several dogs were supplemented with various oils as adjunctive treatments, including MCT and CBD oil, a practice increasingly common in this population 71 .…”

A multicenter randomized controlled trial of medium‐chain triglyceride dietary supplementation on epilepsy in dogs

“…Around one‐third of dogs continue to seizure despite appropriately managed polypharmacotherapy 8‐10 . In addition, behavioral and cognitive comorbidities occur in dogs with epilepsy, 11 such as anxiety 12,13 deficits in spatial memory, 14 or cognitive function 15,16 . Seizures, drug‐related adverse effects along with changes to behavior and cognitive capabilities all contribute to the reduction in quality of life (QoL) for both dogs and their owners 17‐21 .…”

A review of treatment options for behavioural manifestations of clinical anxiety as a comorbidity in dogs with idiopathic epilepsy

“…One veterinary study has looked at the owner-perceived effect of the AED imepitoin on anxiety in dogs with IE but reported no difference between pre-and post-treatment levels (Packer et al, 2017). Regardless of the negative results, this study contributes an important starting point towards the development of potential treatments for dogs with ADCE.…”

“…Central nervous system adverse effects were not individually specified but included ataxia, restlessness, hyperactivity and disorientation. Packer et al (2017) found no change in fear and anxiety-related behavioural scores in 85 dogs before or during treatment for IE with imepitoin, but this could be due to the retrospective nature of the study design or be caused by differences in effect of the drug upon the epileptic brain and the 'normal' brain, particularly for drug-resistant dogs. The use of imepitoin in canine behavioural medicine for the management of sound related fears has been reported (McPeake and Mills, 2017).…”

“…(Charambolous et al, 2016) Imepitoin No change in fear and anxiety-related behavioural scores in 85 dogs before or during treatment for IE with imepitoin. (Packer at al, 2017) ACVIM consensus statement reported no A C C E P T E D M A N U S C R I P T anxiety as an adverse effect of imepitoin. (Podell et al, 2016) Anxiety reported as a less common, dosedependent and reversible adverse effect in a systematic review of 6 monotherapy and 2 adjunctive therapy papers.…”