A review of the medications available for the management of anxiety/fear
Robert Falconer-Taylor BVetMed DipCABT MRCVS
Centre of Applied Pet Ethology www.coape.org
Robert is a veterinary surgeon and partner of the Centre of Applied Pet Ethology (COAPE), the first organisation in the UK to develop government-regulated courses to degree level specifically in companion animal behaviour and training. COAPE also developed the renowned EMRA system used by behaviourists and trainers all over the world, now summarised in their book – EMRA Intelligence: The revolutionary new approach to treating behaviour problems.
Robert is an international consultant to the pet industry and is a member of the International Cat Care Behavioural Advisory Panel.
Robert’s primary academic interests include companion animal cognitive science and emotionality, nutrition and its effects on behaviour, and applied neurophysiology, pharmacology and therapeutics in companion animal behaviour therapy.
As fear is an experience generated in the brain, any effective therapy, regardless of what it is and how it is delivered, MUST ultimately interact with specific receptors that modulate the brain’s fear circuits in some way.
In this article, a range of prescription and non-prescription options are discussed, along with their putative modes of actions and recommendations of use. It should be noted that medications should only be used when environmental management has been undertaken and has not been effective and after careful consideration and possible discussion with a veterinary behaviourist.
Medications should only be used in the short-term management of firework-related and other fears where environmental management has been undertaken and has not had the desired effect of reducing the cat’s fear.
Prescription psychoactive drugs that are used for treating and managing fear-related disorders fall into three main categories – tranquilisers, anxiolytics and antidepressants.
For cats that are otherwise happy, but are adversely affected by fireworks, and where environmental management is not enough, some form of short-term medication is indicated. An effective short term pharmacological intervention should have at least one of the following key modes of action, and preferably both: (a) reduce the immediate fight-flight autonomic arousal, or (b) modulate the impact of fearful events on emotional (amygdala) memory. The purpose of a drug here is not to ‘cure’ the cat, but simply to prevent a progressive escalation of the animal’s fear into a longer lasting negative emotionalstate.
Acepromazine (ACP) should never be used in cats that are fearful because it has no anxiolytic properties whatsoever. As a powerful and indiscriminate dopamine (D2) antagonist it causes a degree of immobilisation, via the nigrostriatal pathways, and drowsiness, via the mesolimbic reward pathways.1
It is for this reason that ACP has been widely used in the past to manage firework phobias in pets – owners perceive the drug ‘a success’ because their animal seems to ‘settle down’. Unfortunately the drug has little effect on the cat’s sensory perception of fear-inducing stimuli and little effect on the cat’s adverse internal emotional response to it. ACP may even render sensory systems more sensitive thereby exacerbating the onset of chronic anxiety/fear.
Acepromazine should not be used in the management of fear in cats as it has no anxiolytic properties, it simply sedates the cat, which will still fear frightened.
The benzodiazepines have both anxiolytic and amnesic properties mediated through different pathways. The anxiolytic effects are mediated through GABAA receptors as agonists. The amnesic effects are less well understood and several mechanisms have been proposed including as GABAA agonsists, NMDA antagonists and platelet activating factor receptor antagonists.
The table below summarises common anxiolytic drugs that may be useful in managing firework and other fears in cats.2-5
Dose: 0.125–0.25mg/kg as required q8–12h.
Test dose: Ideally, owners should be asked to trial their cat on the drug and report back any undesirable side effects (owners should be warned that the tablet can be bitter and cause hypersalivation and also increases appetite) or concerns they may have as the benzodiazepines can cause a paradoxical excitement in some animals.
Effect is dose-dependent: Mildly sedative and muscle relaxing at low doses. Anxiolytic at moderate doses facilitating social interaction. Sedative at higher doses above that required as an anxiolytic facilitating sleep. Amnesic effects are more profound at the higher dose range.
Speed of action: 30 – 60 minutes.
Protocol: There are two scenarios in which the drug can be very useful.
Prophylactic: The owner anticipates when fireworks will start and administers the full dose 1 to 2 hours beforehand while the cat is not showing any signs of fear. Another half dose may be given as the fireworks start if required, however, if the cat is in a fearful state being restraint to be given medication may provoke an aggressive response. If a cat has for example hidden it should be left alone and a new plan for the next expected night of fireworks made.
Interventional: The cat has already become aroused and fearful. The owner gives the cat the full dose followed by another half dose if the cat is still distressed 30 minutes later. The tablets can be made into a paste with a little water to facilitate administration. Again thought should be given as to how the medication is administered in this scenario to avoid owners being injured trying to medicate a fearful cat.
Tolerance and dependence: Alprazolam should not be used over the long-term so this should not be a concern.
Contraindications, adverse drug reactions, drug interactions: See BSAVA (2014) for further prescribing information.1
Dose: 0.2–0.4mg/kg (1.25–5mg/cat) as required q8–12h.
Test dose: As for alprazolam. The effects of alprazolam are generally more reliable than those of diazepam.
Effect is dose-dependent: As for alprazolam.
Speed of action: 30 – 60 minutes.
Protocol: As for alprazolam.
Tolerance and dependence: As for alprazolam.
Contraindications, adverse drug reactions, drug interactions: See BSAVA (2014) for further prescribing information.1 Many of the undesirable side effects associated with diazepam are caused by its primary metabolite N-desmethyldiazepam. Oral diazepam has been associated with a fatal idiosyncratic hepatopathy in some cats.
Some fearful cats may have already progressed to a chronic state of distress which may be accompanied by pathological changes associated with depression. A depressed mood state may be characterised by hiding away and withdrawal from the family, staying in the basket, not wanting to play, subdued reaction to visitors, poor appetite etc (figure 1). Cats in this state 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 primary mode of action of most antidepressants 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 can stimulate the regeneration of neurons in these areas of the brain.6-9
The table below summarises common antidepressant drugs that may be useful in managing firework fears in cats.2-5,10
Antidepressants such as clomipramine take 3-4 weeks to reach an optimum therapeutic level and should only be used as part of a long-term behavioural modification plan following advice from a veterinary behaviourist.
Mode of action: Clomipramine is a member of the tricyclic antidepressant (TCA) class of antidepressants that are structurally derived from the phenothiazine antipsychotics. They broadly have three modes of action – sedation, anticholinergic effects and inhibition of reuptake of monoamines (dopamine, noradrenaline, serotonin) across the presynaptic membrane which increases the availability of the target neurotransmitter. The degree of these effects varies between drugs. Clomipramine has a relatively higher affinity for serotonin reuptake (and noradrenaline to some degree). The primary metabolite desmethylclomipramine also inhibits reuptake of noradrenaline to some degree. In addition, clomipramine has a transient (3 – 5 days) sedation effect in many cats, which may be an advantage in anxious animals.
Dose: 0.25–1.0mg/kg (1/2 a 5mg tablet/cat) q24h.
Speed of action: The effect of the drug on the target behaviour cannot be reliably judged for 3 to 4 weeks after administration begins to allow the drug time to establish a therapeutically optimal state.
Protocol: Used over the long-term as part of a behaviour modification plan, supervised by a qualified veterinary behaviourist liaising with the veterinarian responsible for the cat.
Tolerance and dependence: Weaning off the drug is necessary following long-term use. As a guide, reduce the dose by 50% per week for 2 weeks, then 50% again for a further week, dosing alternate days.
Contraindications, adverse drug reactions, drug interactions: See BSAVA (2014),2 for further prescribing information. The pharmacokinetics of clomipramine and desmethylclomipramine are more variable across feline populations compared with dogs which probably reflects more genetic variability.
Mode of action: Fluoxetine is a member of the selective serotonin reuptake inhibitor (SSRI) class of antidepressants that are structurally derived from the tricyclic antidepressants. That is fluoxetine is a second-generation antidepressant. Although the drug reaches peak plasma levels quickly, its mode of action depends on the production of a new protein molecule that re-shapes target receptors, a process taking 3 to 5 weeks to complete. This accounts for the slow speed of action described below. Fluoxetine has a high affinity for the presynaptic serotonin transporter relative to the noradrenaline transporter, which accounts for its selectivity for serotonin.
Dose: 0.5–1.0mg/kg q24h.
Speed of action: The effect of the drug on the target behaviour cannot be reliably judged for 6 to 8 weeks after administration begins to allow the drug time to establish a therapeutically optimal state.
Protocol: Used over the long-term as part of a behaviour modification plan, supervised by a qualified animal behaviourist liaising with the veterinarian responsible for the cat.
Tolerance and dependence: Weaning off the drug is necessary following long-term use. As a guide, reduce the dose by 25% per week for 3 weeks, then 25% again for a further week, dosing alternate days.
Contraindications, adverse drug reactions, drug interactions: See BSAVA (2014) for further prescribing information.2
The classes of antidepressants mentioned above can be used in combination with the benzodiazepines as part of a behaviour modification and rehabilitation plan. The antidepressant would be used on an ongoing basis along with the anxiolytic used on an as-needed basis when the animal is exposed to unavoidable stressors.
The use of drugs for behavioural modification should ideally be discussed with a veterinary behaviourist.
There are many over-the-counter, non-prescription commercial products advertised as aids for helping cats who are fearful of fireworks. There is also plenty of anecdotal evidence, along with a few studies, that support a degree of effectiveness in many of these products. Therefore, recommending their use is a sensible first option for clients asking for help, bearing in mind that they are unlikely to help cats in extreme states of fear. In addition, the reported anxiolytic effects of most of the compounds discussed below are mediated by binding to GABAA receptors and therefore they are often described as ‘benzodiazepine-like’. The existence of distinct amnesic properties in these compounds is not known, but the superior effectiveness of prescription benzodiazepines in managing maladaptive fear states in many species suggests that effective amnesic properties are not present. This needs to be taken into consideration when counselling owners on the best therapeutic options available for the welfare and rehabilitation of their cats.
Pheromones are naturally occurring compounds released into the surrounding environment. If another animal, of the same species, then comes into contact with the pheromone it can lead to changes in the physiology, the emotional state and therefore the behaviour of that animal. Pheromones are therefore another channel of communication between animals, generally in relation to sexual status and other social states.
Synthetic pheromones are used frequently within veterinary practices to reduce anxiety in cats and effects have been studied on urine marking in the home. They may be useful in the management of firework fears in cats.
Cats deposit the feline facial pheromone F3 fraction around their environment as a familiar boundary marker where it appears to promote a sense of security and help reduce anxiety. Studies on the effects of F3 have been in relation to urine marking,11-16 as well as caging,17 they also support the benefits of synthetic pheromones for reducing anxiety in cats in general including around fireworks.
Selected commercial products: Feliway spray and diffuser.
It should be noted here that aromatherapy, which is usually based on plant-derived essential oils, is not the same thing as pheromonatherapy. Pheromones are natural bodily secretions that are detected by the vomeronasal organ, while essential oils are not secretions produced within the body, and they are detected through an animal’s olfactory system – that is essential oils have a scent whist pheromones do not.
There are a number of naturally occurring ‘benzodiazepine-like’ compounds available advertised as safe anti-anxiety alternatives to prescription pharmaceuticals, for example the herbs Valeriana officinalis, Magnolia officinalis, Passiflora incarnata, Piper Methysticum and Phellodendron amurense (for full discussions on possible therapeutic applications and adverse side effects see references 18-22).
Selected commercial products: Harmonease (Magnolia officinalis, Phellodendron amurense). Calmex (Piper Methysticum).
There are a number of nutraceuticals that have anxiolytic properties. One compound of particular interest is the peptide abundant in cow’s milk, alpha-casozepine. For therapeutic use, these biologically active peptides need to be extracted by tryptic hydrolysis in vitro, which is a process successfully achieved commercially. Alpha-casozepine has ‘benzodiazepine-like’ properties and there is some research that shows the compound to be as effective as selegiline for anxiety disorders in dogs.23,24
Selected commercial products: Calm diet, Zylkene.
L-theanine, extracted from green tea, has ‘benzodiazepine-like’ anxiolytic properties. Trials investigating the use of L-theanine to reduce the fearful behavioural response of dogs towards unfamiliar humans have shown promising results.25
Selected commercial products: Anxitane, Calmex, KalmAid.
Another more familiar amino acid is L-tryptophan, which is the precursor to the neurotransmitter serotonin. It is therefore an essential amino acid normally ingested as part of a balanced diet. It is possible to boost levels of serotonin in the brain by supplementing the diet with additional L-tryptophan and there are a number of proprietary products now available. One study investigating the use of this diet in dogs concluded that the use of the diet ‘improved their ability to cope with stress and may also have reduced anxiety-related behaviour’.25
Selected commercial products: Calmex, KalmAid, Serene-UM.
Inositol is a constituent of cell membranes with no direct anxiolytic or antidepressant properties of its own. Rather it is an important compound for facilitating the activity of other neurotransmitters including serotonin. Inositol is synthesised as needed in the body, but it can also be supplemented through the diet. Studies in humans have shown that such supplementation is effective in treating depression in some cases. A proprietary version of inositol is available as a supplement for dogs too but there is no data on its use in cats.
Selected commercial products: Serene-UM.
Homeopathy and the placebo effect
There is absolutely no evidence that homeopathy is an effective treatment modality and it has no legitimate place in veterinary medicine.26-28 For cats that are fearful, the recommendation to and encouragement of homeopathic remedies to owners as alternative treatments in place of compounds that show clear evidence of effectiveness cannot be justified on the grounds of seriously detrimental consequences for the welfare of the animal.
In this context, the placebo effect is an interesting and powerful phenomenon and it is plausible that if an owner believes that a particular mode of treatment is effective in relieving their cat’s anxiety then subtle changes in the owner’s behaviour may be picked up by the animal and taken as safety cues, although this is less likely in cats compared to dogs as cats are less affected by owner mood. However, chronic anxiety, being a highly unpleasant emotional state, should be treated effectively with behavioural modification and clinically proven medication if needed.
- Rang HP, Dale MM. (2012) Rang & Dale's pharmacology, 7th Ed. Edinburgh: Churchill Livingstone.
- BSAVA. 2014. BSAVA Small Animal Formulary. British Small Animal Veterinary Association / Wiley Publishing.
- Crown-Davis SL, Landsberg GM. 2009. Pharmacology and pheromone therapy. In Horwitz DF, Mills DS. (eds), BSAVA Manual of Canine and Behavioural Medicine, 2nd ed. Chapter 21. British Small Animal Veterinary Association / Wiley Publishing.
- Landsberg GM, Wayne H, Hunthausen L, Lowell J, Ackerman LJ. 2012. Pharmacologic intervention in behavioral therapy. In Behavior Problems of the Dog and Cat, 3rd ed. Chapter 8. Elsevier Health Sciences.
- Overall C. 2013. Pharmacological Approaches to Changing Behavior and Neurochemistry: Roles for Diet, Supplements, Nutraceuticals and Medication. In Manual of Clinical Behavioral Medicine for Dogs and Cats. Chapter 19. Saunders Ltd.
- Anacker, C., Zunszain, P. A., Cattaneo, A., Carvalho, L. A., Garabedian, M. J., Thuret, S., Price, J., Pariante, C. M. (2011). Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor. Mol Psychiatry. 2011 Jul;16(7):738-50.
- Duman, R. (2004). Depression: A Case of Neuronal Life and Death? Biological Psychiatry 2004;56:140–145.
- Sheline, Y. I., Wang, P. W., Gado, M. H., Csernansky, J. G., Vannier, M. W., (1996) Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A. 1996 April 30; 93(9): 3908–3913.
- Vaidya, V. A., Duman, R. A. (2001). Depression – emerging insights from neurobiology. Br Med Bull (2001) 57 (1): 61-79.
- Takano A, Nag S, Gulyás B, Halldin C, Farde L. 2011. NET occupancy by clomipramine and its active metabolite, desmethylclomipramine, in non-human primates in vivo. Psychopharmacology (Berl). 2011 Jul;216(2):279-86.
- Frank D, Erb HN, Houpt KA. (1999) Urine spraying in cats: presence of concurrent disease and effects of pheromone treatment. Appl Anim Behav Sc. 1999;61: 263â€“ 272.
- Hunthausen W. (2000) Evaluating a feline facial pheromone analogue to control urine spraying. Vet Med. 2000;95: 151â€“ 156.
- Mills DS, Mills CB. (2001) Evaluation of a novel method for delivering a synthetic analogue of feline facial pheromone to control urine spraying by cats. Vet Record. 2001;149: 197â€“ 199.
- Mills DS, Redgate SE, Landsberg GM. (2011) A meta-analysis of studies of treatments for feline urine spraying. PloS ONE. 2011;6: e18448.
- Ogata N, Takeuchi Y. (2001) Clinical trial of a feline pheromone analogue for feline urine marking. J Vet Med Sci. 2001;63: 157– 161.
- Pageat P, Gaultier E. (2003) Current research in canine and feline pheromones. Vet Clin North Am Small Animals. 2003;33: 187– 211.
- Griffith CA, Steigerwald ES, Buffington CA. (2000) Effects of a synthetic facial pheromone on behaviour of cats. J AM Vet Med Assoc 2000; 15:1154-1156
- DePorter, T. L., Landsberg, G. M., Araujo, J. A., Ethierd, J. L., Bledsoee, D. L. (2012) Harmonease chewable tablets reduces noise-induced fear and anxiety in a laboratory canine thunderstorm simulation: A blinded and placebo-controlled study. J Vet Behav 7:225-232, 2012.
- Ernst, E. (2007). A re-evaluation of kava (Piper methysticum). Br J Clin Pharmacol. 2007 Oct;64(4):415-7. Epub 2007 Jun 6.
- Hart, B. L. (2005). The evolution of herbal medicine: behavioural perspectives. Anim. Behav. 70, 973–989.
- Lakhan, S. E., Vieira, K.F. (2010). Nutritional and herbal supplements for anxiety and anxiety-related disorders: systematic review. Nutr J. 2010 Oct 7;9:42.
- Tessier, D. J., Bash, D. S. (2003) A surgeon's guide to herbal supplements. J Surg Res. 2003 Sep;114(1):30-6.
- Beata, C., Beaumont-Graff, E., Diaz, C., Marion, M., Massal, N., Marlois, N., Muller, G., Lefranc, C. (2007) Effects of alpha-casozepine (Zylkene) versus selegiline hydrochloride (Selgian, Anipryl) on anxiety disorders in dogs. J Vet Behav 2:175-183, 2007.
- Palestrini, C., Minero, M., Cannas, S., Berteselli, G., Scaglia, E., Barbieri, S., Cavallone, E., Puricelli, M., Servida, F., Dall'Ara, P. (2010). Efficacy of a diet containing caseinate hydrolysate on signs of stress in dogs. J Vet Behav 5:309-317.
- Araujo, J. A., de Rivera, C., Ethier, J. L., Landsberg, G. M., Denenberg, S., Arnold, S., Milgram, N. W. (2010) ANXITANE® tablets reduce fear of human beings in a laboratory model of anxiety-related behavior, J Vet Behav 5:268-275, 2010.
- Cracknell NR, Mills DS. (2008) A double-blind placebo-controlled study into the efficacy of a homeopathic remedy for fear of firework noises in the dog (Canis familiaris). Vet J. 2008;177: 80– 88.
- Cracknell, NR, Mills, DS. (2011) An evaluation of owner expectation on apparent treatment effect in a blinded comparison of 2 homeopathic remedies for firework noise sensitivity in dogs. J Vet Bheav: Clin Appl Res. 2011;6: 21– 30.
- Overall, KL, Dunham, AE. (2009) Homeopathy and the curse of the scientific method. The Veterinary Journal. 2009;180: 141– 148.