KNOWLEDGE SUMMARY

Keywords: ANXIETY; CANINE; DOGS; FEAR; IMEPITOIN; NOISE PHOBIA

Does imepitoin reduce signs of fear and anxiety in dogs frightened by loud noises?

Hannah McNicholas, BVSc MSc(CAB) KPA-CTP ABTC-ATI MRCVS^1*

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¹ Alongside Animals, Burbage, Marlborough, United Kingdom, SN8 3AJ
* Corresponding author email: Hannah.mcnicholas@alongsideanimals.co.uk

Vol 11, Issue 3 (2026)
Submitted 30 Apr 2024; Published: 14 Aug 2026
DOI: https://doi.org/10.18849/ve.v11i3.745

PICO question

In adult pet dogs with a sensitivity to sudden loud explosive noises, does treatment with imepitoin, compared to no medical treatment, reduce levels of fear and anxiety?

Clinical bottom line

Category of research

Treatment.

Number and type of study designs reviewed

Two papers were critically reviewed. Both were double blind randomised placebo-controlled clinical trials.

Strength of evidence

Moderate.

Outcomes reported

Imepitoin given orally twice daily to adult dogs who were sensitive to loud noises such as fireworks or thunderstorms reduced owner rated levels of fear and anxiety responses when compared to placebo. Owner satisfaction with imepitoin treatment was mostly good, but a proportion of dogs developed mild-to-moderate side effects including ataxia, appetite changes, lethargy, and emesis during treatment.

Conclusion

In adult pet dogs with a sensitivity to sudden loud noises, treatment with imepitoin, compared to no medical treatment, may reduce owner-rated levels of fear and anxiety responses in their dogs. Imepitoin appears to be generally well tolerated by dogs, is considered easy to administer by owners and can positively improve the welfare of dogs who show fear and anxiety in response to loud noises including fireworks and thunderstorms. Whilst no serious adverse effects were noted, a high prevalence of side effects were observed in the reviewed studies which were carried out using the manufacturer’s recommended dose for noise phobia. These side effects were shown to be unacceptable to some owners, resulting in reduced compliance and satisfaction with treatment. Clinicians should proactively discuss potential side effects of imepitoin with owners, particularly if used at the manufacturer's recommended dose, and consider starting at a lower twice daily dose of 10 mg/kg and titrating up to 30 mg/kg as required.

How to apply this evidence in practice

The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources.

Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

Clinical scenario

During a routine visit a client mentions to you that her normally calm 4-year-old Labrador is increasingly fearful of loud noises. They live near to farmland where regular shoots are held, and last year he became so agitated by the gunshots that she worried he might injure himself. She has tried making him a safe den to hide in and ignoring his behaviour, although this is challenging. In addition to this she has used calming diffusers, herbal tablets, flower essences, and a pressure vest, none of which made much difference. She did plan to help him using sound therapy as a vet had previously suggested but had not had chance to use it yet. With the shooting season starting again and Fireworks Night approaching, she asks whether there are any tablets she can give for a few days at a time to alleviate signs. You have used short-term alprazolam in the past for other noise phobic dogs, but wonder about the effectiveness of imepitoin, which is licensed for this problem.

The evidence

Two prospective double-blind randomised placebo-controlled clinical trials addressed the PICO question. Both used samples of client-owned dogs who were evaluated in the home environment. Engel et al. (2019) examined using imepitoin for dogs with noise phobia who had previously reacted to firework noises, whereas Perdew et al. (2021) specifically examined imepitoin use for storm anxiety.

The strongest evidence comes from a multicentre study by Engel et al. (2019) with a sample size of 226 dogs (in full analysis set), which demonstrated a statistically significant reduction in owner-reported fear and anxiety behaviours. These behaviours, however, were assessed using a scale which had not been validated separately from this study (Mills et al., 2012). Perdew et al. (2021), a smaller study of 45 dogs (in the intention-to-treat analysis set), showed a reduction in owner-reported fear and anxiety in the imepitoin-treated dogs. The small sample size and high withdrawal rate from the imepitoin group, however, affects the validity and transferability of their results. In both studies high numbers of mild-to-moderate adverse events (side effects) in the imepitoin groups potentially led to a degree of unblinding and the introduction of bias, particularly as both studies relied on subjective owner assessment for results. Taking these limitations into consideration, alongside the low number of studies which answer the PICO question, the evidence was considered moderate.

Summary of the evidence

Engel et al. (2019)

Effectiveness of imepitoin for the control of anxiety and fear associated with noise phobia in dogs

Aim: To determine the effectiveness and safety of imepitoin compared to placebo for reducing anxiety and fear associated with canine noise phobia.

 

Perdew et al. (2021)

Evaluation of Pexion ^® (imepitoin) for treatment of storm anxiety in dogs: A randomised, double‐blind, placebo‐controlled trial

Aim: To assess the efficacy of imepitoin compared to placebo for the treatment of dogs with a history of storm anxiety.

 

Appraisal, application and reflection

An excessive fear of loud noises is a common problem in the UK canine population with between 25–49% of dogs affected; despite this, many owners are unaware of the treatment options available (Blackwell et al., 2013). Desensitising programmes utilising recordings of fear-eliciting sounds, alongside short-term management changes, are recommended to manage noise sensitivity (Sherman & Mills, 2008). These programmes should be started a minimum of 60 days in advance of anticipated events and accompanying instructions followed carefully (Levine et al., 2007) which in practice, is not always possible for some owners. Short-term psychopharmaceutical intervention for distressed dogs is therefore warranted on welfare grounds. Imepitoin is one of the three licensed psychopharmaceuticals available.

Two papers were considered suitable for appraisal, both randomised placebo-controlled trials (Engel et al., 2019; Perdew et al., 2021). Notably, both studies were funded by Boehringer Ingelheim, who manufacture the veterinary licensed form of imepitoin. The study by Engel et al. (2019) directly assessing fear and anxiety caused by fireworks had the larger sample size of the two studies appraised. Results were given for the full analysis set (FAS)  226 dogs and included 18 dogs who had less than the full number of treatment doses and one dog in the placebo group who received concomitant treatment. This may, however, reflect nonexperimental scenarios where compliance is not always perfect. The study reported that fear and anxiety behaviours were statistically significantly reduced in the imepitoin group versus placebo group at all time points. Additionally, behaviours indicating fear or anxiety were reduced in dogs given imepitoin versus placebo, which was concluded in a later study to be a clinically relevant difference (Mills et al., 2020). Significantly lower mean modified Lincoln Sound Sensitivity Scale (LSSS) scores (Mills et al., 2012) were seen in the imepitoin group in the Engel et al. (2019) study at maximum firework intensity. Their explanatory box and whisker plot, however, illustrates the variability of response with some dogs responding better than others. The modified LSSS questionnaire used in both studies aims to increase the objectivity of the data collected (Mills et al., 2012) and appeared to be reliable when it was initially validated during the Engel et al. (2019) study (Mills et al., 2020).

The paper by Perdew et al. (2021) examined client-owned dogs with fear and anxiety elicited by storms. Whilst the sound of fireworks most commonly triggers behavioural fear reactions, it has been suggested that dogs that have a phobia of fireworks are highly likely to also display a fear of gunshots and thunder (Blackwell et al., 2013; Riemer, 2019). Perdew et al. (2021) reported a reduction in weekly survey scores (assessment of all storms over the previous week) from baseline in dogs receiving imepitoin. A reduction was also seen in the placebo group with 26.7% of owners (compared to 78.6% in the imepitoin group) agreeing that the treatment reduced their dog’s signs of fear and anxiety. This percentage is similar to the approximately 25% of owners in the placebo group who rated treatment as ‘excellent’ or ‘good’ in the study by Engel et al. (2019), suggesting a caregiver placebo effect. Perdew et al. (2021) also reported significant differences between storm log scores for imepitoin and placebo groups. However, no figures (other than a line graph) or  p-value are included in the results, and the wide 95% confidence interval of –∞ to –0.03813 reflects the small sample size and uncertainty about any conclusions drawn.

Both studies reported high incidences of mild-to-moderate adverse events (side effects) particularly in the first week. In Engel et al. (2019) 48% of the imepitoin group compared to 10% in the placebo group had side effects including 35% of dogs developing ataxia, although the ataxia was reported to resolve in three quarters of cases over the 24 to 48 hours following treatment inception. Whereas Perdew et al. (2021) reported that 80% of the imepitoin group compared to 13% in the placebo group experienced adverse events including ataxia, appetite changes, and somnolence. As a result, 10/30 (33.3%) dogs taking imepitoin in the Perdew et al. (2021) study withdrew. Such a high number of dogs lost potentially invalidates any benefit of randomisation as participants are not lost equally and randomly from both groups, introducing bias into the per protocol analysis (Lachin, 2000). Similarly, the necessity to impute data for an undisclosed proportion of the imepitoin group could also affect the validity of the intention-to-treat results (Streiner & Geddes, 2001). In addition, 90% of owners in the Perdew et al. (2021) imepitoin group correctly guessed what group their dog was in, suggesting possible unblinding (Forbes, 2013) potentially affecting the validity of results which relied upon owner report.

The potential distress caused to owners by observing signs of fear and anxiety in their dogs responding to loud noises may have affected the ability of some of the owners in these studies to accurately record their dog’s behaviour. Scoring of owner-recorded videos by canine behaviour experts could have been used to detect signs of noise phobia potentially missed by owners (Van Belle et al., 2023). However, it is important to note that even with good inter- and intra-observer reliability, adequate blinding of the video assessors may have been difficult given the degree of noticeable side effects seen in the imepitoin treatment groups (Tuyttens et al., 2014).

The rationale for Engel et al. (2019) choosing a dose of 30 mg/kg twice daily was to rapidly establish an efficacious serum imepitoin concentration and based in part on a case series by McPeake & Mills (2017) which included 14 dogs with unspecified noise sensitivities. Out of those 14 dogs, only five were on a dose of around 30 mg/kg twice daily at the final follow up after 11 to 19 weeks. McPeake & Mills (2017) proposed that for dogs diagnosed with fear-anxiety disorders doses of 20 mg/kg imepitoin twice daily may be sufficient for anxiolysis. Indeed Engel et al. (2019) lowered daily doses of medication to mitigate ataxia in seven cases (five in imepitoin group, two in placebo group) although when and by how much was not described.

Whilst not directly related to the PICO question, the potential side effects of imepitoin are of note with respect to an owner’s willingness to continue the treatment, and to the possible impact that being ataxic or vomiting may have on a dog already experiencing an aversive event. Trialling lower doses for efficacy without side effects before titrating upwards could therefore be considered an appropriate approach.

Furthermore, a small pilot study with no placebo control by Muñoz Amezcua et al. (2024) examined an individualised dose titration approach for imepitoin, reporting a reduction in signs of anxiety during storms using doses ranging from 10 to 30 mg/kg twice daily. During the 12-week study period, the initial dose of 10mg/kg twice daily was increased every two weeks if there was a perceived lack of response to 20mg/kg twice daily or 30mg/kg twice daily.  Whilst lower doses were effective for some dogs, an increase in dose was required for many others. By the end of the study, 1/33 dogs remained on the 10mg/kg dose, 3/33 on the 20mg/kg dose and 11/33 on the 30mg/kg dose. The remaining dogs withdrew due to a perceived lack of effect or adverse effects. As in the appraised studies, the rate of mild-to-moderate adverse events including ataxia, appetite changes, and ‘irritability/aggressive behaviour’ was high and was notably more prevalent in dogs receiving 20 mg/kg imepitoin twice daily. Further large-scale trials are needed to confirm whether doses lower than that recommended by the manufacturer can maintain therapeutic effect, whilst minimising side effects.

Imepitoin is one of three drugs currently licensed and available for treating noise phobias in the UK and should be considered in preference to unlicensed medication. The evidence for using imepitoin is considered moderate due to limitations including a low number of randomised placebo-controlled studies, variability of results, subjective assessment bias, and high incidence of side effects potentially affecting the validity of results. Clients need to be made aware of any possible side effects and that treatment outcomes may vary, necessitating dose titration for some dogs. Any dose alterations or treatment failures should be recorded in clinical records in such a way that their prevalence can be monitored within a practice setting, and discussions had amongst clinicians about whether for example a different starting dose to that recommended should be used.

Methodology

Search Strategy

 

Exclusion / Inclusion Criteria

 

Search Outcome

 

Acknowledgements

The author would like to thank Maureen O’Mara for her advice and support.

ORCiD

Hannah McNicholas: https://orcid.org/0009-0006-3695-3796

Conflict of Interest

The authors declare no conflicts of interest.

References

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