Dexmedetomidine for dogs with noise aversion – how effective is it?

 
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Dexmedetomidine is widely used in injectable form as a pre-anaesthetic agent and for sedation and analgesia in dogs and cats. Since 2015, it has been authorised in the form of an oromucosal gel for dogs (brand name Sileo) for the alleviation of acute anxiety and fear associated with noise (Sileo SPC). This module examines the evidence on dexmedetomidine for this newer indication. By doing this module you will:

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

  • be aware of the clinical evidence in support of its use in managing noise aversion

  • understand how to use dexmedetomidine for treating noise aversion in dogs

  • know the adverse effects of dexmedetomidine in dogs treated for noise aversion

  • be aware of key information to tell clients

Related modules:

Noise phobia – compare before deciding

Imepitoin for noise aversion in dogs

Fireworks – can alpha-casozepine help?

Fireworks are the most commonly reported cause of noise aversion (phobia) in dogs in the UK (PDSA Paw Report 2011; Blackwell et al 2013). However, many other noises also reported to cause significant problems including thunderstorms, gunshots and traffic noise (Sherman & Mills 2008; Storengen & Lingaas 2015). Symptoms of noise aversion 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, herbal remedies and drugs. 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 (Sileo) and imepitoin (Pexion). 

Dexmedetomidine is a selective alpha-2 adrenergic receptor (adrenoceptor) agonist. In injectable form it is used as a pre-anaesthetic agent and for sedation and analgesia (usually in combination with an opioid) in dogs and cats (BSAVA 2017). 

Dexmedetomidine works by binding to alpha-2 adrenoceptors. In the brain, it decreases the release of noradrenaline from noradrenergic neurons and causes a reduction in the activity of the sympathetic nervous system which is involved in controlling anxiety, arousal and sleep, blood pressure and heart rate. The sedative effects are mediated through the decreased amount of noradrenaline in the locus coeruleus, the predominant noradrenergic nucleus, situated in the brainstem. Rodent models of fear and anxiety have shown that dexmedetomidine has a dose-dependent action in the locus coeruleus in the brain, so that a small reduction in noradrenaline release results in anxiolysis, while a larger reduction results in sedation and hypnosis; it is assumed that this also applies to dogs (CVMP 2015).

Sileo is an oromucosal gel containing dexmedetomidine hydrochloride 0.1mg (equivalent to 0.09 mg dexmedetomidine) in 1mL of translucent green gel. The amount of dexmedetomidine reaching the circulation after oral administration is poor due to extensive first-pass metabolism in the liver. However, when the drug is applied to the mucosal membranes of the oral cavity, there is better bioavailability as a result of absorption via the oral mucosa and avoidance of first-pass metabolism. The mean bioavailability of oromucosal dexmedetomidine is 28% and peak levels occur after about 30–40 minutes (Sileo SPC).

The half-life of dexmedetomidine in dogs after oromucosal administration ranges from 0.5 to 3 hours. Metabolism, mainly in the liver, accounts for more than 98% of its elimination. The metabolites, which show no or negligible activity, are mainly excreted in the urine; a small amount is excreted in the faeces (Sileo SPC).

Dose-finding studies in dogs have indicated that lower exposure to dexmedetomidine, through a combination of a lower dose and oromucosal application rather than parenteral administration, results in a lower level of sedation than is seen with doses used for sedation (CVMP 2015). 

The main evidence on the efficacy of dexmedetomidine for treating noise aversion in dogs comes from one published randomised, double-blinded, placebo-controlled trial (Korpivaara et al 2017). This was part of the data package used to gain the marketing authorisation for this indication (CVMP 2015). The trial was carried out on a New Year’s Eve. It included 187 dogs with a history of anxiety and fear caused by fireworks. They were randomised to receive dexmedetomidine oromucosal gel (at a dose of 125 micrograms/m2) or an equivalent volume of placebo gel, applied to the oral mucosa, as needed up to five times. In all, 182 dogs (89 in the dexmedetomidine group and 93 in the placebo group) received at least one dose of treatment and were included in the study results.

Owners applied the gel either pre-emptively 1 hour before the anticipated start of the fireworks, immediately when the fireworks were heard, or when the dog began to show signs of anxiety and fear. They were able to reapply the gel after at least 2 hours if the dog began to show signs of anxiety and fear again. The efficacy of the treatment was assessed using two main outcomes, both assessed by the owners: the overall effect of the treatment on behaviour compared with the previous New Year’s Eve without treatment; and the behavioural sum score, which assessed the signs and extent of anxiety and fear (maximum score of 48 with lower scores indicating less distress).

There was a better overall treatment effect with dexmedetomidine compared to placebo (odds ratio in favour of dexmedetomidine was 3.4, 95% confidence intervals 1.95 to 5.99, p<0.0001). A higher proportion of dogs in the dexmedetomidine group had an excellent or good treatment effect compared to the placebo group (72% vs. 37%). Quite a large placebo effect was seen, possibly because of an expectation of a beneficial effect (caregiver placebo effect), which may have affected the owners’ behaviour with consequent positive effects on the dogs’ behaviour. It should be noted that the outcome measure used is subjective and based on owners’ recollection of the dogs’ behaviour in the previous year, which is prone to recall bias. When dogs that showed signs of potential sedation were excluded from the analyses, the results still showed that dexmedetomidine had a beneficial effect compared with placebo. The researchers interpreted this as showing that dexmedetomidine had an anxiolytic rather than a sedative effect. In 17% of dogs, dexmedetomidine was judged to have no effect, or to worsen the dogs’ behaviour compared to the previous year (vs. 44% with placebo).

Dogs on dexmedetomidine also had lower overall behavioural sum scores than those on placebo, indicating less distress. One hour after the first dose the behavioural score fell by 1.1 with dexmedetomidine (vs. a fall of 0.5 with placebo; not statistically significant); while after the second dose the score fell by 4.7 points (vs. 1.2 with placebo; p=0.0003). Dogs on dexmedetomidine displayed less panting, trembling, vocalising, pacing and inappropriate urination than those on placebo (p<0.05 for each sign). Although the study reports that the owners recorded the intensity of fireworks the dogs were exposed to, this is not reported in relation to behaviour in the results. Owners also assessed functional alertness by calling their dog and scoring their observations (related to responsiveness and ability to stand and walk). More than 85% of dogs were classed as fully functional with no apparent differences between groups (p>0.05). Seven dogs in the dexmedetomidine group and two in the placebo group were unable to stand up and walk when called.

In the main clinical trial, the most common reported adverse effect was vomiting. This was reported in four out of 89 dogs (4%) receiving dexmedetomidine vs. one of 93 dogs (1%) on placebo (Korpivaara et al 2017). The summary of product characteristics (SPC) reports that there may be transient paleness of mucous membranes at the application site due to peripheral vasoconstriction. It also states that other commonly-reported adverse events in clinical trials (in more than 1 but fewer than 10 in 100 dogs) were sedation and urinary incontinence. Uncommon adverse reactions (in more than 1 but fewer than 10 in 1,000 dogs) were anxiety, periorbital oedema, drowsiness and signs of gastroenteritis (Sileo SPC).

As the effect of dexmedetomidine is related to dose, it is possible that a small dog exposed to a large overdose would be sedated. However, on the basis of study results, this would be expected to be transient and followed by a full recovery in a healthy dog (CVMP 2015). In the case of an overdose, the effects can be reversed with the use of atipamezole; dosage guidance for this is provided in the Sileo SPC.

The SPC recommends giving the first dose as soon as the dog shows the first signs of anxiety, or when the owner detects a typical stimulus (e.g. fireworks or thunder) for eliciting anxiety or fear in the dog. Typical signs of anxiety and fear include panting, trembling, pacing (frequent change of place, running around, restlessness), seeking people (clinging, hiding behind, pawing, following), hiding, trying to escape, freezing (absence of movements), refusing to eat food or treats, inappropriate elimination and salivation (Korpivaara et al 2017; Sileo SPC). 

The gel should be applied onto the oral mucosa between the dog’s cheek and gum. Sileo comes in an oral syringe that delivers the gel in 0.25 mL increments for a range of doses for dogs weighing from 2kg to 100kg. Each increment is shown as one dot on the plunger; the dosing table gives the number of dots to be administered corresponding to the dog’s bodyweight. If the total dose required is more than 6 dots (1.5ml), half should be applied to the oral mucosa on one side of the mouth and half on the other side. If the fear-eliciting event continues and the dog shows signs of anxiety and fear again, another dose may be given 2 hours after the previous dose. The product can be dosed up to five times during each event. The pharmacological response to alpha-2 agonists (such as dexmedetomidine) may be reduced in animals that are extremely nervous, excited or agitated because of the high levels of endogenous catecholamines (Sileo SPC). 

Dexmedetomidine is contraindicated in dogs with severe cardiovascular disorders and those with severe systemic disease (graded as American Society of Anaesthesiologists Physical Status Classification III–IV), such as end stage renal or liver failure (Sileo SPC).

The safety of administering the product to puppies younger than 16 weeks old, dogs over 17 years of age, and during pregnancy and lactation is not known. If other central nervous system depressants are given concurrently, they might potentiate the effects of dexmedetomidine and therefore an appropriate dose adjustment should be made (Sileo SPC).

To our knowledge, dexmedetomidine gel has not been compared in a clinical trial with imepitoin (the other product licensed for use in dogs with noise aversion) or been tested for efficacy in noise related phobias other than to fireworks.

We found no published controlled trials assessing the use of dexmedetomidine in dogs in which imepitoin has not been effective in reducing fear and anxiety during a noise event.  One veterinary behaviourist we consulted reported using dexmedetomidine gel as and when needed in dogs on long term twice daily imepitoin for noise fears when the imepitoin was helping with general noise sensitivities but insufficient at times of increased noise (e.g. on fireworks night). 

There is scope for incorrect use of the product, for example if it is wrongly placed in the mouth and the dog swallows the gel, or if the syringe locking mechanism has not been engaged properly and an overdose is given. There are specific instructions on opening the packaging and dose selection – to avoid potential overdosing and ensure child-safety. Therefore, the product should only be prescribed if the client can use it competently. There is a clear and helpful package leaflet and an online video showing how to use the product correctly. In the main clinical efficacy trial for dexmedetomidine most owners (85%) found the product easy to administer (Korpivaara et al 2017). However, in dogs that are not accustomed to handling procedures, administration has been reported to be more difficult and so there is an important role for the veterinary team to play in giving advice on how to teach a dog to accept such handling (McPeake et al 2017).

The client should be informed that the medicine is intended to be absorbed from the inside of the mouth and that if the gel is swallowed it will be ineffective. To prevent the gel from being swallowed, the dog should not be fed or given treats within 15 minutes after administration of the gel. If the gel is swallowed the dog can be given another dose, if necessary, a minimum of 2 hours after the previous dose (Sileo SPC). 

Dexmedetomidine can be absorbed through damaged skin, mucous membranes (mouth/gums), and eyes, so handlers should avoid skin, eye or mucosal contact (Plumbs 2018). The SPC advises that the person administering the gel should wear impermeable disposable gloves (these are not provided with the product). Dexmedetomidine is not considered to be a skin irritant (CVMP 2015). Pregnant women should avoid contact with the product because systemic exposure to dexmedetomidine can cause uterine contractions and decreased foetal blood pressure (Sileo SPC). 

The oral syringe must be kept in the carton to protect it from light. The shelf life after first opening the immediate packaging (removal of the cap) is 4 weeks (Sileo SPC). 

Clients should be told that sedation may occur if the dose is exceeded. If sedation occurs, the dog should be kept warm and the client should contact the vet.

Dexmedetomidine is available as a gel for administering to dogs via the buccal mucosa for reducing anxiety and fear associated with noise. In one randomised controlled trial, 72% of owners considered it had a good or excellent effect in reducing fear and anxiety caused by New Year’s Eve fireworks. In the trial, dexmedetomidine appeared to be well tolerated with vomiting being the most commonly reported adverse effect. It is crucial that the client is able to follow the instructions on handling and use of the product. Drug treatment is not a substitute for behavioural management of noise phobia in dogs. 

Literature search

We searched RCVS Knowledge Discovery Service (including PubMed) and VetMed Resource (CAB Abstracts) on 2 April 2019 using the terms (dexmedetomidine OR Sileo*) AND (fear* OR anxi* OR noise OR phobi* OR fright* OR nervous* OR scared) AND (dog OR dogs OR canine OR canines OR canis)

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How we produced this module

Our modules start with a detailed outline and electronic literature search. We commission a collaborating author, who is a specialist in the module topic, to write a draft module. The collaborating author on this module was  Andrea Tarr, Director of Veterinary Prescriber, a specialist in medicines evaluation. The draft was circulated unsigned to topic specialists, practising first-opinion vets and pharmaceutical companies. 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. 

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) (2015). CVMP assessment report for Sileo (EMEA/V/C/003764/0000) International non-proprietary name: dexmedetomidine [online]. https://www.ema.europa.eu/en/documents/assessment-report/sileo-epar-public-assessment-report_en.pdf [Accessed 30.04.19]

Imepitoin for noise aversion in dogs. Veterinary Prescriber April 2019. https://www.veterinaryprescriber.org/subscribers-content/imepitoin-for-noise-aversion-in-dogs

Korpivaara M et al. (2017) Dexmedetomidine oromucosal gel for noise-associated acute anxiety and fear in dogs – a randomised, double-blind, placebo-controlled clinical study. Vet Record 180: 356

McPeake K et al. (2017) Noise sensitivities in dogs: a new licensed treatment option. Vet Record 180: 355

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

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

Plumb’s Veterinary Drugs [online]. https://www.plumbsveterinarydrugs.com [Accessed 30.04.19]

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/en/documents/product-information/sileo-epar-product-information_en.pdf [Accessed 15.7.19]

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