In the first and second article of this series, I looked at how the normal ‘fear system’ works and how this emotional system can become a long-standing, maladaptive anxiety and depression disorder. In this third article of the series, I take an evidence-based approach to selecting and using prescription pharmaceuticals as part of a well-constructed behavioural therapy plan for dogs whose lives have been ruined by fireworks.
IMPORTANT INFORMATION, PLEASE READ FIRST
This information is important and relevant for 2 audiences –
PLEASE SEE BOX 1 AT THE END OF THIS ARTICLE FOR THE INFORMATION YOU MUST BE AWARE OF
Although the information provided in this article is for dog owners, it is also relevant for cat owners. Additional information for cat owners can also be found at the following ICC resources –
In 2013, the charity Dogs Trust revealed the results of an owner-based survey they carried out on the effects of the Autumn and Winter fireworks season on pet dogs in the UK. The numbers are staggering; around 72% of dogs are frightened of fireworks to some degree and one in ten of these dogs is so traumatised that they have had to have veterinary treatment (Dogs Trust, 2012). Dog owners are also affected with 90% reporting that they change their routine over this period in an attempt to protect their dogs where they can from exposure.
Owners have a legal duty of care under the Animal Welfare Act 2006 to ensure that their pets do not suffer unnecessarily which includes fear (DEFRA, 2013). More often than not the first port of call for an owner with a noise-sensitive dog is their veterinary practice, and all too often this is at the eleventh hour and too late to implement any kind of controlled counter-conditioning program.
The problem with the term ‘phobia’
In companion animal behaviour, ‘phobia’ is a commonly used term in relation to fear-related behaviour problems. In human psychiatric medicine, a phobia is an ‘acute-onset and irrational high-arousal-level fear reaction to a specific stimulus’. A phobia is either FULL-ON or FULL-OFF, there is no in-between setting. Phobias in humans are wide-ranging and, in many cases bizarre (search the internet for examples). For example, phobias to buttons, baked beans, fried eggs, ducks, pigeons, garden gnomes, and, of course more obvious phobias such as spiders and snakes. To be clear, these reactions are not trivial. Sufferers often have their lives ruined by their phobias and end up on long-term medication as a result.
From a dog’s perspective, his acute, adverse reaction to a firework being discharged nearby is completely rational. All mammals have hard-wired innate fear response, or reflex, as described by the LeDoux “The Difference Between The Quick and the Dead” circuit discussed in the first and second articles of this series. However, there are no innate reflexes in any species related to buttons, baked beans, fried eggs etc. So, as you can see, there is a semantic difference between a bizarre and irrational phobia in a human and a perfectly rational phobia in a dog. For this reason, COAPE defines the term ‘phobia’ differently.
We defined the term ‘anxiety’ in the second article of this series as “an internalised state, generated by the brain, in anticipation of a fearful event THAT MAY NEVER OCCUR (COAPE, 2013)”.
In companion animal behaviour, we define a phobia as “a chronic anxiety disorder within which are learned and persistent high-level peaks of fear (hypothalamic-pituitary-adrenal (HPA) axis activation discussed in the first article of this series),that are disproportionate to the actual level of danger present (the fireworks in this case)”. The persistent nature of a phobia means that the dog remains in this highly-aroused and aversive state for some time after the event has past.
So, a phobia in a dog IS NOT irrational, but it IS maladaptive, in that it is of no biological value to the dog whatsoever, and it ruins the dog’s life. So a phobia is a huge concern to the dog’s welfare.
The main problem with dogs that for those that start of simply being alarmed and frightened by fireworks, for some the fear will progress into an anxiety disorder, and for many of those the condition will progress into a phobia. Repeated exposure to this stimulus, even just once or twice a year, just reinforces this maladaptive learned response and the phobia gets progressively worse.
In short, these dogs will NEVER GET BETTER ON THEIR OWN, BUT THEY WILL GET WORSE.
What the owner sees is a dog that becomes progressively more shut-down and dysfunctional as time goes by. If the dog’s exposures are sporadic and infrequent, and perhaps lives in a busy household, the family just may not notice the subtle changes in the dog’s reactivity, demeanour and enthusiasm for life around every-day ‘normal’ stimuli such as the ping of the microwave alarm. Or the owner may simply dismiss this as ‘getting older’. So, it can take several years before the problem becomes so severe that it begins to disrupt the owners own lifestyle at which point they seek professional advice. The other end of that advice is often and dog’s vet, or a behaviourist.
The problem for the dog – and the owner – is that there is no ‘quick-fix’.
There is no pill or supplement that will miraculously switch off the dog’s well-exercised but seriously dysfunctional FIGHT-FLIGHT survival system and then repair the potential brain damage that it has caused, as discussed in the second article of this series.
For this reason it is reasonable to classify noise phobias in dogs as a
chronic degenerative behaviour disorder that requires a long-terms, properly managed treatment program that will require behaviour modification and, in many cases, prescription medication and/or other forms of adjunctive therapy.
Using prescription medication to manage firework fears
Fear is an experience generated in the brain so any effective therapy, regardless of what it is and how it is delivered, MUST ultimately interact with specific receptors in the brain that modulate the fear circuits in some way.
For dogs who show signs of fear around thunder storms, fireworks etc., but are bright and happy at other times and can go about their daily business normally, owners need to take these early warning signs very seriously. Unfortunately, for many dogs this does not happen, primarily because the dog appears to make a full recovery when the event has past. However, as discussed in Part 2 of this series of articles, fear conditioning is cumulative. Every exposure to the feared stimulus causes small changes in the brain’s connections, specifically in the fear-processing limbic system (see Part 1 and Part 2 of this series of articles).
In some dogs (let’s call them GROUP A), these changes in connections, or rewiring of the brain, are adaptive and eventually result in the dog ignoring noisy fireworks etc. without any intervention by the owner. This is the normal process of habituation in action.
In other dogs (we’ll call these dogs GROUP B), this rewiring is maladaptive and the dog inappropriately learns that fireworks etc. are dangerous, and that they should be avoided at all times. As discussed in Part 1, the chronic, insidious and cumulative nature of fear conditioning explains why it generalises to other environmental stimuli so readily.
The problem for dog owners is that it is not always obvious from the dog’s behaviour – until it is too late – which group of dogs (A or B), their dog belongs to.
Therefore, in an ideal world, ALL owners of dogs showing early signs of reactivity around fireworks etc. would be proactive and get to work with a qualified behaviourist on a desensitisation/counter-conditioning program OUTSIDE OF THE FIREWORK SEASON, along with sound CDs’ etc. For all of the GROUP A dogs, this exercise will help them through the habituation process.
It will also work for some of the GROUP B dogs, especially if it is started early enough in the history of the dog’s fear reactions, and while the dog is young. However, for some of the GROUP B dogs, desensitisation/counter-conditioning alone will not be enough.
The good news is that, because these dogs are under observation, a good behaviourist will spot the lack of progress and therefore be in a position to make an informed change in their behavioural approach to the dog’s management. One appropriate change in the behavioural management of these dogs is a pharmacological one.
It is worth reminding ourselves at this point that fear conditioning is special (LeDoux, 1996). 6 months hard graft working with a dog through a desensitisation/counter-conditioning program can easily be unravelled in a few seconds if the dog is exposed unexpectedly to the feared event.
Unfortunately, this is a common set-back for fireworks because they are used so often for celebrations through the year. For this reason, for all dogs living in at-risk’ areas of the country where the use of fireworks cannot be reliably predicted, it is entirely appropriate for a good behaviourist to consider including pharmacological support from the start of their desensitisation/counter-conditioning program.
So, where environmental management is not enough because of the frequency or unpredictability of fireworks being discharged, some form of short-term medication should be considered. When a dog is exposed to fearful events, effective short term pharmacological intervention should have at least one of the following key modes of action, and preferably both:
- REDUCE FEAR REACTION: Reduce the immediate, reactive fear-related FIGHT-FLIGHT emotional ‘spike’.
- REDUCE IMPACT ON MEMORY: Mitigate the negative impact of repeated fearful events on emotional (amygdala) memory (see Part 1 of this article). Also see BOX 2.
The purpose of a drug here is not to ‘cure’ the dog, the desensitisation/counter-conditioning program does that. The purpose of the drug is simply to prevent an adaptive fear response progressing on to a maladaptive phobia as a result of unavoidable repeated exposures. So these kinds of drugs should be used on an ‘as-needed’ basis, in the same way we may use paracetamol to help manage a headache.
For owners of at-risk GROUP B dogs, it all comes down to planning and the pre-emptive use of the medication. For example, in your area the Guy Fawkes celebrations means that fireworks are most likely to be discharged during the evenings between 30th October through to 10th November. So, you would routinely give your dog the medication at dusk, ideally before you draw the curtains and prepare for the evening. In addition, you should carry the medication with you at all times in case the dog experiences an unexpected fear-inducing event whilst out on a walk.
The benzodiazepine group represent the drugs of choice here because they have both anti-fear (anxiolytic) and memory interfering (amnesic) properties. Arguably, the most infamous benzodiazepine – for all the wrong reasons – is flunitrazepam (Rohypnol), the ‘date-rape’ drug. Flunitrazepam is a very effective anxiolytic, blocking the fear response and at the same time interfering with memory consolidation. So the individual remembers very little of what happened while under the influence. After some notorious cases of misuse as a recreational ‘party drug’ in the late 1990’s – 2000’s, it fell out of favour and is now a controlled, Schedule 3 drug. However, the Rohypnol story will help you appreciate just how powerful these drugs are and how useful they can be where blocking the fear response and interfering with the formation of conditioned fear memories is an enormous benefit.
The two benzodiazepines most commonly used in dogs are diazepam and alprazolam. Although around 40 times less potent than flunitrazepam, they are nonetheless still very effective in many cases if used properly. The key difference between diazepam and alprazolam lies in their reliability and their mode of action on memory.
Diazepam only interferes with anterograde memory consolidation, that is memories of events that occur after the drug is in the dog’s system at therapeutic levels.
Alprazolam, on the other hand, suppresses both anterograde and retrograde memory, that is memories of events that occurred both before and after the drug was in the dog’s system at therapeutic levels.
Figure 3 above shows the short-term and long-term effects fireworks can have on a GROUP Bdog over the course of one evening between 15:00 through to 06:00 the following morning.
- AROUSAL LEVEL: A plot of the dog’s minute-by-minute emotional fear arousal level over the course of the evening.
- LONG-TERM MEMORY TRACE: Representation of the cumulative effects of the dog’s arousal level on the long-term, forever memory of that evening.
- RED ARROW: Time the fireworks start.
- BLUE ARROW: Time the fireworks ended.
- GREEN ARROW: Time the owner gave the dog the benzodiazepine drug (middle and bottom rows only).
- NO MEDICATION: Top row. This represents what happens to the dog’s emotional state and long-term memory with no medication available. This row represents the baseline control.
- DIAZEPAM: Middle row. This represents what happens to the dog’s emotional state and long-term memory when given diazepam 3 hours after the fireworks started.
- ALPRAZOLAM: Bottom row. This represents what happens to the dog’s emotional state and long-term memory when given alprazolam 3 hours after the fireworks started.
As you can see in Figure 3, both benzodiazepine drugs are superior to no drug at all in managing the dog’s negative emotional state through the evening and in reducing the negative impact this will have on the dog’s long-term memory.
Alprazolam clearly has an advantage over diazepam because, even though the owner was 3 hours later with the dosing it still worked because of its effect on recent retrograde memory (memory consolidation is a slow process). Note that in this example, it is common for an owner to come home later than expected, only to find her dog in an acutely stressed state, panting, salivating and pacing up and down because her neighbours have been unexpectedly letting off fireworks for someone’s birthday celebrations.
The anxiolytic and amnesic properties of these benzodiazepine compounds are quite separate and distinct and operate through different neural pathways. The anxiolytic properties of the benzodiazepines are mediated through the brain’s gamma-Aminobutyric acid (GABA) receptors, while their amnesic properties are mediated through N-methyl-D-aspartate (NMDA).
GABA receptors are broadly inhibitory when activated and alcohol is the most familiar and widely used drug to recreationally activate them. This explains why having a glass of wine is relaxing and then sedating and sleep-inducing after the 3rd and 4th glass. Benzodiazepines bind to a different site on GABA receptors where they have a more specific effect of suppressing anxious feelings.
NMDA receptors are a type of glutamate receptor which are broadly excitatory when activated, so they are effectively the polar opposite of GABA receptors. Benzodiazepines block memory formation by inhibiting specific NMDA receptors in the hippocampus (see part 1 of this article for more information about memory).
The degree of activation of GABA and inhibition of NMDA receptors by different benzodiazepine drugs is ‘manufactured’ into the molecule, depending on what the therapeutic applications of the drug are destined to be (for full discussions on possible modes of actions of the benzodiazepines on memory see Anand et al., 2007; Beracochea, 2006; Curran et al., 1994; Kilac et al., 1999; Singh et al., 1998; Tan et al. 2011).
The sedative dexmedetomidine has recently been licensed for the ‘alleviation of acute anxiety and fear associated with noise in dogs’ Korpivaara (2017). Marketed as Sileo, this drug comes as a palatable gel in a syringe. This allows the owner to instil a small amount of the gel into the dog’s mouth between the gums and the teeth, rather like squeezing a bit of toothpaste onto a brush.
The way dexmedetomidine works is quite different from the benzodiazepines. It blocks the release of noradrenaline right at the back of the brain in the pons.
This part of the brain is one of the first to become aroused when an animal responds to an incoming stimulus (see Part 2 for more details about fear processing in the brain). It is responsible for the genesis of the fear reaction and the chain of events that lead to stimulation of the hypothalamic-pituitary-adrenal (HPA) axis and the release of stress hormones, as described in Part 1. Dexmedetomidine has no specific effects on memory consolidation like the benzodiazepines, but of course it helps prevent fear-memory formation in the first place by blocking upstream HPA arousal levels. In serious cases it could be used alongside a benzodiazepine drug.
For some GROUP B dogs, their poorly managed fear will have progressed where they are in a state of constant, fluctuating arousal. These dogs are dysfunctional and elements of their wider or even local environment may have taken on the role as predictors of fear. Such dogs have developed an anxiety disorder with phobia, as described above, and this becomes a major welfare issue which cannot be ignored.
In addition to the benzodiazepine group of drugs, these dogs should be considered as candidates for additional quite specific, pharmacological support over the longer term. The rationale for this is because of the link between chronic anxiety states and damage to brain areas and neurotransmitter systems found in depression (see Part 2 of this series of articles). A depressed mood state can account for many of the behavioural changes associated with chronic, unresolved anxiety states such as –
- withdrawal from the family
- staying in basket
- not wanting to play
- subdued reaction to visitors
- poor appetite etc.
Dogs that are both anxious and depressed can be extremely difficult to engage and motivate, making any kind of rehabilitation program difficult if not impossible without some kind of pharmacological support.
The discovery in the 1950s to 1960s of the link between depression and the down-regulation of the monoamine neurotransmitters serotonin and noradrenaline in the brain stands as one of the great milestones of knowledge laying the foundations for effective treatments of clinical depression in humans (see Rang and Dale, 2012).
It should be remembered here that most of the research, and then the development of antidepressant drugs has been carried out using animal models because the emotional systems of all mammals are very similar if not identical. The primary mode of action of antidepressant therapy is to increase the availability of monoamine neurotransmitters in the brain’s emotional circuits responsible for the regulation of mood states.
More recently, a body of evidence has emerged demonstrating that, in addition to the restoration of the monoamine neurotransmitters and the subsequent elevation of mood state, many antidepressant drugs also reverse the damage of neurons in the brain and stimulate their regeneration. The belief that brain cells, or neurons can never be replaced is not true (Anacker et al., 2011; Duman, 2004; Sheline et al., 1996; Vaidya and Duman, 2001).
There are many antidepressant drugs available for humans with a great deal of variation in their influence on neurotransmitters such as serotonin, noradrenaline, dopamine and other modulating psychoactive neurotransmitters. The tricyclic antidepressant drug clomipramine, licensed as Clomicalm for dogs, primarily increases the availability of serotonin and noradrenaline in key areas of the brain. This can be hugely beneficial in the rehabilitation of long-standing noise-phobic dogs for the reasons describe above. The selective serotonin reuptake inhibitors (SSRI’s) represent another varied group of antidepressant drugs, of which fluoxetine in the most widely prescribed in dogs.
Long-term depression can also have an enormous negative impact on a dog’s motivation. The neurotransmitter, dopamine is a major player in the brain’s reward pathways and drugs that increase its availability can also be very useful. Selegiline, licensed as Selgian for dogs, does just this. In general, dopamine agonists will increase motivation and exploratory behaviour and they are also important in the facilitation of learning and memory.
Selegiline cannot be used concurrently with the antidepressants described above. However, clomipramine, fluoxetine and selegiline can all be used with the benzodiazepines.
Treatment of anxiety disorders in dogs is a slow process and requires medication and desensitisation/counter-conditioning behaviour modification work over many months. Dogs need to remain on appropriate antidepressant medication throughout the process until significant progress has been made, at which point a gradual weaning process off the medication can begin.
Benzodiazepine drugs should also be available for use with these dogs when needed to mitigate the damaging effects on the behavioural modification program of unavoidable exposure to phobic-inducing events such as firework celebrations.
Never use ACP in Fearful dogs
Antipsychotics such as Acepromazine (ACP) and Chlorpromazine are sedatives, the former being used widely in dogs as part of the clinical management of anaesthesia in veterinary practice. Although dogs given ACP appear to be relaxed, the drug is not in fact an anxiolytic and has no anti-anxiety properties whatsoever.
These first-generation antipsychotics are powerful and indiscriminate dopamine blockers that have 2 significant effects –
- Cause a degree of immobilisation: Parkinson’s disease in humans is caused by a progressive destruction of dopamine-producing neurons in a small area of the brain called the substantia nigra. The substantia nigra is responsible for converting an individual’s thoughts of the desire to move into the signals that are actually sent to the muscles to move. Patients with advanced Parkinson’s disease are frozen like statues. The tragedy of this horrible disease is that, even though they cannot move, these patients are fully aware of their environment and react to it emotionally. However, they are unable to express their feelings, either good or bad, to others through the look on their face, or through more obvious behaviours such as avoidance.
- Cause a profound drowsiness: As described above, dopamine is also a major player in the brain’s reward pathways and in the feelings of general motivation and enthusiasm. Indiscriminately blocking these important neural pathways causes disorientation and drowsiness.
It is for these reasons that ACP has been widely used in the past to manage firework phobias in dogs – owners perceive the drug ‘a success’ because their dog seems to ‘settle down’.
Unfortunately the drug has no affect at all on the dog’s sensory perception of the scary sounds and light and no effect on the dog’s adverse internal emotional response to it.
ACP may even render to dog’s sensory systems more sensitive to external stimuli thereby exacerbating the onset of a noise phobia in the future. It could be argued that the dog would be better off having nothing at all than be given ACP during the firework season.
BOX 1: IMPORTANT INFORMATION, PLEASE READ FIRST
This information is important and relevant for 2 audiences –
There are a number of seminars, courses etc. available offering to teach you how to use prescription medicines for treating a range of behaviour problems in dogs. If you are a dog owner or a canine professional attending such a course, you need to ensure the following –
WHY IS THIS IMPORTANT?
The first reason is obvious. The second reason is less obvious, but it is really important.
It is common for some people attending these seminars to ask the person running the course for specific advice on using a prescription medicine for a current and ongoing behaviour problem in a dog. For example, an owner may ask about their own dog, or a behaviourist may ask about a client’s dog they are treating.
Other people attending the seminar may not have a specific dog in mind at the time, but they may want to use the information they obtain about using prescription medicines sometime in the future, either in their own dog, or a client’s dog that presents with a behaviour problem.
When someone attending the seminar takes steps to get hold of the recommended prescription medicine for a dog, the first port of call will be a veterinarian, because vets are the only professionals who can prescribe these drugs. There are strict laws regulating the use of prescription medicines in the UK, summarised below. Because of these regulations, the vet will want to speak to the person who recommended the drug. This is why the person running the course, or seminar needs to take responsibility for the information they provided to you. Specifically, they need to provide their contact details to all attendees of the course so these can be passed on to the vet, should they be required.
From time to time, COAPE receives requests from people who have attended pharmacology seminars or courses because the person running the course referred them to us. In effect, COAPE is delegated without our consent or knowledge as the ‘responsible person’ for the information provided at the seminar.
This is unprofessional, unethical and rude.
COAPE cannot discuss the use of prescription medicines with attendees of pharmacology courses where we have no means of knowing the quality of the information provided. We are also unable to liaise with vets on behalf of course attendees for the same reason. By doing so, COAPE would effectively be agreeing to be the ‘responsible person’, with all the legal implications this may have.
SUMMARY OF PRESCRIPTION MEDICINES REGULATION IN THE UK
The use of prescription medicines is tightly regulated in the UK. Prescription medicines include all the drugs that cannot be bought ‘over the counter’ from a pharmacist without a written prescription. Prescription medicines can only be used in animals when they are prescribed by a veterinarian.
Furthermore, the animal needs to be under the care of that vet, which means that the animal needs to have been seen and physically examined recently by the vet. In addition, the vet must also maintain accurate and detailed clinical records about the pet and its medical history.
The choices that the vet makes when choosing an appropriate prescription medicine for an animal is also regulated. Where there is a choice of several drugs available for treating a particular condition, but only 1 of them is specifically licensed for use in animals, the vet must choose that drug over the others.
If she does not, then she needs to be able to provide a reasonable argument supporting her choice. The cost of the drug is not a reasonable argument, even though an alternative human-licensed drug may therapeutically be perfectly suitable. The vet is breaking the law if she does this.
Very few drugs are licensed for use in behaviour problems in pets, namely clomipramine, selegiline and dexmedetomidine in the UK, and fluoxetine in the United States.
There are many other prescription drugs licensed for humans that can also be very effective in treating behaviour problems in pets. It is absolutely fine for the vet to prescribe these drugs, but this must be done in accordance with the ‘prescribing cascade’. In addition, because these drugs do not carry a specific veterinary license, the prescribing vet is obliged to obtain informed consent from the pet’s owner before issuing the prescription.
The Royal College of Veterinary Surgeons (RCVS) states – “Informed consent, which is an essential part of any contract, can only be given by a client who has had the opportunity to consider a range of reasonable treatment options, with associated fee estimates, and had the significance and main risks explained to them.”
For more information about the regulations governing the use of prescription medicines, click HERE
For more information about informed consent, click HERE
|BOX 2: TYPES OF AMNESIA
Amnesia, or loss of memory, can occur as a complete amnesia where the
RETROGRADE AMNESIA: Damage to the areas of the brain that store previously learned memories, primarily the cerebral cortices and the amygdala, can lead to retrograde amnesia. Here, the individual is no longer able to remember previous learning and experiences. This kind of amnesia is often on a gradient proportional to the age of the memories. Recent memories are the most severely affected, but the individual will generally be able to remember more and more the further back in time the memories go.
ANTEROGRADE AMNESIA: Damage to the areas of the brain that form, or consolidate new memories, primarily the hippocampus, can lead to anterograde amnesia. If memories cannot be consolidated, they cannot be stored, so the individual ceases to be able to remember new experiences. In short, the individual is no longer able to learn anything new. This kind of amnesia generally has a sharp cut-off point.
Amnesia can also be caused by interfering with the neurotransmitters in the brain that are responsible for instigating memory formation or retrieval. This can be achieved deliberately by drugs such as the benzodiazepines.
© copyright Robert Falconer-Taylor, 2017
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Images used in this article
- Fireworks, Thames, London. Christine Matthews [CC BY-SA 2.0 (https://creativecommons.org/licenses/by-sa/2.0)], via Wikimedia Commons.
- Tablets. By Pöllö (Own work) [CC BY 3.0 (http://creativecommons.org/licenses/by/3.0)], via Wikimedia Commons
- Short term and long-term effects of fireworks on dogs. Copyright © COAPE, 2017.
- Types of amnesia (BOX 2). Copyright © COAPE, 2017.
Available with the publication of the final part of this 4-part series of articles.