Imepitoin in Behavioral and Neurobehavioral Medicine

Imepitoin was developed as an anticonvulsant and has been used as an anticonvulsant in dogs alone or with other antiepileptic (AE) medications.^1,2 It has also been used for situational anxiety,³ including anxiety that accompanies idiopathic epilepsy;⁴ a number of canine fear and anxiety applications;⁵ and fear of fireworks and storms.^6,7 It is licensed in Europe as Pexion (Boehringer Ingelheim, pexion.co.uk) as an atypical AE for dogs not responding to traditional AEs and for the situational treatment of fear of noises. It is licensed in the United States only for the latter application, again as Pexion, but not distributed in the U.S. at time of publication. To be successful in alleviating noise reactivity associated with anxiety and fear, it must be given by mouth twice a day, starting 2 days before the anticipated fear-provoking event (e.g., fireworks) and including the day of the event for 3 days of treatment.

Mechanism of Action

Imepitoin, an imidazolone structurally similar to phenytoin, is a partial agonist of the benzodiazepine site of the gamma-aminobutyric acid A (GABA_A) receptor. As a partial agonist, it binds to activate the receptor, but at only partial efficacy relative to full agonists like diazepam and clonazepam (12% to 21% of the effect exerted by diazepam).⁸ Like other low-affinity compounds, it has a short receptor interaction time and is easily displaced by full agonists. 

Imepitoin also blocks voltage-gated calcium channels in a dose-dependent manner and may stimulate the barbiturate binding site of the GABA_A receptor. These actions activate the GABA_A receptor, stimulating inhibition of activity, and can counteract the excitatory effects of the amino acid glutamate. Glutamate spikes have been implicated in stroke; idiopathic epilepsy affecting the hippocampus and frontal cortex in humans, rodents, and cats; and behavioral pathologies involving impulsive components. 

Efficacy

Epilepsy

Expression of GABA_A receptors is affected in epilepsy; accordingly, medications that affect various aspects of the GABA_A receptor and potentiate its inhibitory effect may act as AEs. Drug-resistant epilepsy may be due to the activity of large numbers of GABA_A receptor subtypes that function differently. 

Imepitoin was effective in nonrefractory, newly diagnosed idiopathic epilepsy in dogs in a clinical trial.¹ In an open-label trial using imepitoin as an add-on medication to phenobarbital in dogs with drug-resistant idiopathic epilepsy, the combination of imepitoin and phenobarbital decreased monthly seizure frequency when imepitoin was started at dosages as low as 5 mg/kg PO q12h.² In one treatment group, if imepitoin was not effective, phenobarbital was added, with effects similar to those of supplementing the original dose of phenobarbital with imepitoin. This result suggests intrinsic patient population heterogeneity in activation of the GABA_A receptor in dogs considered drug resistant. Whether this population heterogeneity is due to functional variability in receptor subtypes is unknown. Supplementation was not effective in a group of dogs with cluster seizures,² suggesting that multiple mechanisms for seizures exist in these clinically polymorphic variants. 

Fear and Anxiety

Imepitoin has been variously dosed and trialed for the treatment of nonspecific canine fears and anxieties,⁵ canine generalized anxiety disorder,³ comorbid anxiety in dogs with idiopathic epilepsy,⁴ fear of noises associated with fireworks,⁶ and fear of noises associated with storms.⁷

In an open-label, non-blinded, non–placebo-controlled case series study of 20 dogs with various fear- and anxiety-related concerns, only 4 of which did not have an association with noise, 19 dogs were treated with a behavior modification program and imepitoin starting at 10 mg/kg and increasing to a maximum of 30 mg/kg PO q12h for 11 to 19 weeks.⁵ Results for the 17 dogs that finished the study were based on self-reported, client-scaled assessments at baseline and after treatment and on client diaries, which were used to calculate average weekly fear-anxiety reaction scores and average weekly global fear-anxiety scores. Clients reported lower reaction scores between baseline and week 1 and baseline and week 11. There were 7 adverse events, including 2 related to sedation.

In a placebo-controlled, randomized, double-blind, single-site study, dogs with generalized anxiety disorder were treated for 3 days at 20 mg/kg PO q12h.³ Assessment was through response to a series of 14 provocative tests at baseline and after treatment and comparison of plasma cortisol levels for 54 dogs. No significant effect was seen for the behavioral tests. A statistically significant reduction in serum cortisol levels was associated with imepitoin treatment, and initial serum cortisol levels correlated with severity of the condition. Adverse events were reported in 13 dogs in the imepitoin group and 12 in the control group. Ataxia was reported only in dogs in the imepitoin group.

An online survey of 85 owners of dogs with idiopathic epilepsy treated with imepitoin for comorbid anxiety evaluated effects on dog-directed fear, human stranger–directed fear, non-social fear, pain sensitivity, and separation-related behavior.⁴ Treatment was for a minimum of 4 weeks. No statistically significant differences were noted in any measures when scores obtained before and after treatment were compared. Seizure frequency did decrease. Dogs received imepitoin at dosages of 10 to 37.5 mg/kg PO q12h. Adverse events primarily occurred within the first 2 weeks of treatment; the most common adverse effects were polyphagia and sedation.

A placebo-controlled, randomized, double-blind, multisite study of 238 dogs with fear of fireworks used a 16-item owner-completed assessment of fear and anxiety to measure response to treatment.⁶ Dogs in the imepitoin group were treated for 3 days at 30 mg/kg PO q12h. A statistically significant effect was noted for dogs in the imepitoin group. Ataxia occurred in more than 20% of the treated dogs, with half of the dogs taking 2 or more days to recover.

Longer-term effects of imepitoin on fear associated with storms were evaluated in a double-blind, placebo-controlled, randomized study in which 30 dogs received imepitoin (30 mg/kg PO q12h) for 28 days.⁷ Effects were evaluated using owner ratings of intensity for 16 common behaviors exhibited by dogs fearful of noises. Summary scores were compared with baseline and between groups. Clients also kept storm logs about their dog’s behavioral responses. Mild/moderate adverse effects were seen in 26 dogs, 24 of which were in the treatment group (80% of imepitoin-treated dogs), and ataxia was the most common adverse event. Adverse events resulted in withdrawal of 10 imepitoin-treated dogs from the study; there were no withdrawals in the control group. Imepitoin was statistically superior to placebo in both the logs and the scored ratings at weeks 2 and 4, but not continuously. Clients significantly reported beneficial effects on non-storm noises.

Clinical Applications

The established clinical applications for imepitoin include interventional use as a supplemental medication for refractory or incompletely responsive idiopathic epilepsy in newly diagnosed dogs, prophylactic use over 3 days for dogs with a known heightened reactivity to or fear of noise when a known noise trigger is expected (e.g., fireworks), and both prophylactically and interventionally for dogs with known fear of storms where exposure is regular or chronic over at least a month.

Recommended Dosage

Pexion is available (in Europe) in 100- and 400-mg scored tablets and dosed by weight at a range of 10 to 30 mg/kg every 12 hours. For idiopathic epilepsy, the dosage starts at 5 to 10 mg/kg PO q12h and increases by 50% to 100% weekly depending on degree of resolution.^1,2 In the study of dogs with generalized anxiety disorder, the dose was 20 mg/kg PO q12h for 3 consecutive days.³ Similar dosing is recommended for fear of noises, although the commonly recommended dosage is 30 mg/kg PO q12h for 3 consecutive days for fireworks⁶ (the licensing dosage) and up to 28 days for storms.⁷

Pharmacokinetics

High plasma levels of imepitoin are found within 30 minutes of dosing, with maximum plasma levels not reached in dogs until 2 to 3 hours after administration due to slow absorption associated with low solubility.⁸ Plasma binding is only 55% and terminal half-life is 2 hours in dogs. Feeding and gender have no effect on outcome. Most (>90%) is excreted in feces. No adverse signs were seen after 28 days of chronic treatment followed by abrupt cessation, and imepitoin induction of cytochrome P-450 enzymes appears minimal, rendering metabolism-induced drug interactions unlikely, but interactions with CYP1A1 are possible. Induction of liver enzymes does not occur at therapeutic dosages.⁸

Benefits and Adverse Effects/Contraindications

Imepitoin is not water soluble and may benefit from low pH environments. Inhibition of stomach acid by proton pump inhibitors (i.e., omeprazole) may interfere with the action of imepitoin. Notable adverse effects reported in published trials include sedation and ataxia lasting for days.^3-7 Because the medication must also be given for 3 days, the sedation and ataxia must be considered as adverse events in any discussion of usage and cannot be viewed as transient. 

Conclusion

No one medication works for all dogs in all circumstances in behavioral medicine. Having a choice of licensed compounds, each of which may help an individual dog at different times or help different dogs, benefits patients. 

Imepitoin, while licensed a few years ago, is still not broadly available globally. 

Disclosure

Dr. Overall has consulted for all of the drug companies that develop behavioral medicine for dogs and cats. She consults for Orion Pharmaceuticals and helped design the study that licensed Sileo.