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Microsoft word - landsberg - drug therapy.rtf

Drug Therapy in Veterinary Behavior – Show me the Evidence
Gary Landsberg DVM, DACVB, DECAWBM
North Toronto Veterinary Behaviour Specialty Clinic, Thornhill, ON, Canada
Psychotropic drugs and natural products can be useful for reducing the signs associated with phobic, panic or chronic anxiety and to improve trainability in situations where the pet is anxious, fearful,
or aroused. Drugs may also have a dramatic effect when there is brain pathology, as with compulsive
disorders, impulse dyscontrol or cognitive dysfunction syndrome. Drugs may also be useful for feline
urine marking and some forms of aggression. However, drugs do not change the relationship with the
stimulus so that concurrent behaviour modification will also be needed to desensitize, countercondition
and train desirable responses.

Show me the evidence

Evidence based decision making allows treatment options to be selected by using the available evidence together with the clinician’s expertise as to the patient, client and problem. Using the Oxford Centre for Evidence Based Medicine Scoring System, the weakest level of evidence is in vitro research, case based studies or expert opinion without critical appraisal.1 The highest level would be a systematic review with homogeneity of randomized control trials (RCT). However, with few published trials for most veterinary behavior drugs there is no real access to this process. In fact, to date only one meta-analysis examining the effects of therapeutic agents on urine marking in cats has been published.2 The importance of using RCT’s to validate efficacy is of particular importance in veterinary behavior where the placebo effect can reach 50% or higher. In one study of separation anxiety over 65% of dogs on fluoxetine improved compared to over 51% of the placebo group.3 In veterinary behavior much of our drug information is extrapolated from human literature; however, drug metabolism and receptor effects vary between species and between individuals. For example the clearance half life diazepam and its intermediate metabolite nordiazepam in dogs is 2.5 and 3 hours in cats 5.5 and 21 hours, and 20-50 and up to 200 hours in humans. This can lead to inaccurate assumptions with respect to dose, duration of effect, contraindications and side effects. Therefore, drugs licensed for pets should first be considered since there is data with respect to safety, efficacy, side effects, contraindications, toxicity and pharmacokinetics. In addition, technical support from the manufacturer provides additional expertise, especially in the event of adverse events. There are also legal requirements in some jurisdictions to prescribe veterinary drugs first (prescribers cascade). When dose, compliance or availability is an issue compounding might be considered; however, stability, storage and bio-availability are a concern. In addition, for transdermal medications, one study
found the bioavailability of fluoxetine to be 10% of oral dosing, while systemic absorption of amitriptyline
and buspirone was negligible.4,5 A physical examination and blood and urine tests should be part of a
minimum database prior to dispensing drugs.
Finding the evidence

While a meta-analysis of randomized placebo controlled clinical trials is the gold standard for assessing the efficacy of a therapeutic agent, few if any drugs or natural products in veterinary behavior
have been subjected to such rigorous standards. Recently laboratory models have been developed for
dogs and cats to evaluate learning and memory, fear of noises and fear of humans, allowing for the
assessment of drugs, supplements and behavior products in a controlled environment with minimal
subject variability, validated measures, and removal of owner bias These models have proven invaluable
in validating the efficacy of a number of diets, supplements and drugs for use in dogs and cats.6-10

Antidepressants

Antidepressants may reduce anxiety, panic and impulsivity. They may take 4 weeks or longer to achieve full therapeutic effect since initial reuptake inhibition will induce down-regulation of postsynaptic receptors. They cause little or no sedation and are unlikely to inhibit learning or memory. Clomipramine and fluoxetine are licensed for dogs for separation anxiety.11,12 There is also evidence of efficacy for clomipramine (a tricyclic antidepressant) and selective serotonin reuptake inhibitor (SSRI) for the treatment of compulsive disorders and urine marking in cats.13-18 SSRI’s might also be useful for generalized anxiety, fears and phobias and some forms of aggression in pets.19-21 SSRI’s or clomipramine on an ongoing basis might be combined with a benzodiazepine or trazodone on an as needed basis prior to fear or anxiety evoking events (e.g. fear, anxiety, aggression).22-25 The primary mechanism of action of TCA’s is blockade of serotonin and noradrenaline reuptake with varying degrees of anticholinergic, antihistaminic and alpha adrenergic effects. Clomipramine is the most selective inhibitor of serotonin reuptake of the TCA’s. Doxepin has marked antihistaminic effects and moderate effects on noradrenaline but minimal effects on serotonin. The alpha-adrenergic effects of imipramine may aid in improving sphincter control in pets with enuresis, or conflict, excitement or submissive urination while also ameliorating anxiety. Amitriptyline has moderate effects on both serotonin and noradrenaline, and strong antihistaminic and anticholinergic effects. However, there are no studies that have demonstrated a significant effect of these other tricyclic antidepressants in pets.26,27 Serotonin syndrome is a serious and potentially fatal concern which may arise when antidepressants that inhibit serotonin reuptake are used at high doses or in combination with other drugs
that may increase serotonin. They should not be used concurrently with other antidepressants or MAO
inhibitors such as selegiline and amitraz. Caution should also be used when combining with St. Johns
Wort, amphetamines, and possibly tramadol, tryptophan, metoclopramide, or dextromethorphan as well
as serotonin receptor agonists such as buspirone and bromocriptine. Signs of serotonin syndrome
include confusion, shivering, shaking, hyperthermia, tachycardia, diarrhea, twitching, tremors, seizures,
coma and death. Since, SSRI’s inhibit cytochrome P-450 enzymes they can lead to increased toxicity if
combined with drugs metabolized by these enzymes.28

Anxiolytics

Buspirone is a serotonin receptor agonist and dopamine agonist. It has been used for mild fear and anxiety and feline urine marking.29 It is non-sedating, does not stimulate appetite, does not appear to inhibit memory and may take a week or more to reach effect. Adding buspirone to an SSRI or TCA might increase the pool of available serotonin. Since anxiolytics such as buspirone or benzodiazepines may disinhibit, they could potentially contribute to an increase in aggression. Benzodiazepines potentiate the effects of GABA, an inhibitory neurotransmitter. They cause a decrease in anxiety, hyperphagia, and muscle relaxation but may cause paradoxical excitability and may have a rebound effect on withdrawal. They reach peak effect shortly after each dose and can be used alone or in combination with other drugs on an as needed basis (e.g. prior to departure or storms).24,30 In one study diazepam was very effective or somewhat effective in 67% of anxiety-related behavior cases, primarily as adjunctive therapy in dogs with thunderstorm fears and separation anxiety.30 When doses of 0.8 mg/kg or greater were used, there were greater reports of increased activity.30 Diazepam may be effective in the reduction of feline urine marking but comparatively less than fluoxetine or clomipramine.29,31 Benzodiazepines may also be useful for counterconditioning especially in victim cats both to reduce anxiety and increase appetite. Rare cases of hepatotoxicity have been reported with diazepam in cats.32 Since clonazepam, oxazepam and lorazepam have no active intermediate metabolites they may be “safer’ with respect to hepatic metabolism. Beta blockers, such as propranolol reduce physiologic signs of anxiety by blocking noradrenaline effects (heart rate, respiratory rate, trembling). They may therefore be useful in combination with drugs that diminish behavioral signs. 30 More recently, clonidine a selective alpha-2 agonist that blocks noradrenaline and therefore autonomic responses of anxiety, has been used together with SSRI’s for situational use about 1.5 hours prior to the event (and up to twice daily) for fear or territorial aggression, separation anxiety, nocturnal barking, or storm and noise phobias.33 At higher doses it can cause sedation. Trazodone is a serotonin 2A antagonist-reuptake inhibitor (SARI). It may be useful as an adjunctive treatment to other behavioral medications such as SSRI’s or TCA’s for generalized anxiety, separation anxiety, noise phobias, some forms of aggression.23 Since it can be calming after a single dose, it might be used on an as needed basis for situational anxiety (e.g. veterinary visits, car rides, separation anxiety). Anticonvulsants
Anticonvulsants may be indicated when clinical signs (e.g. spinning, tail chasing, hyperesthesia) might be caused by a seizure, a focal (partial) seizure or for persistent post-ictal signs such as aggression. In one case series 5 of 7 spinning bull terriers responded to phenobarbital.34 Since focal seizures may be indistinguishable from compulsive disorders, a therapeutic response trial may warranted. Temporal lobe (limbic) epilepsy, may present with mood alterations, hallucinatory behavior, self-trauma or aggression associated with ictal, postictal or interictal stages. Phenobarbital has been used alone or in combination with other behavioral drugs (e.g. benzodiazepines, propranolol, selegiline) for behavioral calming prior to a stressful or phobic event (e.g. veterinary visit, thunderstorm) or on an ongoing basis. Clonazepam and potassium bromide have been used in the treatment of sleep behavior disorders (RBM).35,36 Levetiracetam might be particularly useful for focal seizures (partial epilepsy) as well as for anxiety, stress, panic, and mood disorders and Tourettes.37 Gabapentin can be used in combination with SSRI’s for impulse control, noise phobias and neuropathic pain. Pregabalin can also be used as an anticonvulsant in dogs, with possible applications for anxiety and neuropathic pain.38 Carbamazepine may act as a mood stabilizer and for some forms of explosive types of aggression in dogs.39 Neuroleptics
Neuroleptics such as acepromazine are dopamine agonists that decrease motor function at the basal ganglia, elevate prolactin and may reduce aggression. Phenothiazines have sedating effects but
do not reduce anxiety.

Progestins

Medroxyprogesterone and megestrol acetate have been used for androgen influenced behaviors including aggression to urine marking.31,40 However they have the potential for causing gynecomastia,
mammary tumors, adrenal and bone marrow suppression, acromegaly and diabetes.

Selegiline

Selegiline is an MAOB inhibitor which enhances catecholamine transmission. While it is used in North America for canine cognitive dysfunction syndrome, in Europe it is used for the treatment of
“emotional disorders”. In one study dogs with chronic stress and high anxiety associated with stereotypic
and displacement behaviors and autonomic signs had high prolactin levels, while dogs with acute fears
had lower prolactin levels. Therefore selegiline might be more effective for chronic stress while fluoxetine
might be more effective for acute anxiety.41 Selegiline combined with propranolol, alprazolam and
behavior modification was effective for social and sound phobias.30

NMDA Antagonists
Altered glutaminergic neurotransmission may be a factor in the pathogenesis of compulsive disorders, in which case blocking glutamate sensitive NMDA with drugs such as memantine, amantadine
or dextromethorphan may be effective therapeutic agents alone or together with SSRI’s.42-44 However
dextromethorphan may be less reliable, due to its short half-life, rapid clearance and variable absorption
in dogs.45 NMDA antagonists may also be useful as adjunctive therapy for pain management.


Centre for Evidence Based Medicine, University of Oxford: http://www.cebm.net/index.aspx?o=1025 Mills DS, Redgate SE, Landsberg GM. 2011. A meta-analysis of studies of treatments for feline urine spraying. PloS ONE 6(4): e18448. doi:10.1371/journal.pone.0018448 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0018448 Landsberg GM, Melese P, Sherman-Simpson B, et al. The effectiveness of fluoxetine chewable tablets in the treatment of canine separation anxiety. J Vet Behav 2008: 3: 11-18 Ciribassi J, Luescher A, Pasioske KS, et al. Comparative bioavailability of transdermal versus oral fluoxetine in healthy cats. Am J Vet Res 2003; 64: 994-8 Mealey Kl, Peck KE, Bennett BS et al. Systemic absorption of amitriptyline and buspirone after oral and transdermal administration to health cats. J Vet Intern Med 2004; 18, 43-46 Araujo JA, de Rivera C, Ethier JL et al. 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Sherman-Simpson B, Landsberg GM, Reisner IR et al. Effects of Reconcile (Fluoxetine) Chewable Tablets plus behavior management for canine separation anxiety. Vet Ther 8, 18-31, 2007 12. King JN, Simpson BS, Overall KL, et al. Treatment of separation anxiety in dogs with clomipramine: Results from a prospective, randomised, double-blind, placebo-controlled, parallel-group multicenter clinical trial. Appl Anim Behav Sci 2000;67:255-275 13. Pryor PA, Hart BL, Cliff KD, et al. Effects of a selective serotonin reuptake inhibitor on urine spraying behavior in cats. J Am Anim Hosp Assoc, 2001;219, 1557-1561 14. Hart BL, Cliff KD, Tynes VV, Bergman L. Control of urine marking by use of long-term treatment with fluoxetine or clomipramine in cats. J Am Vet Med Assoc, 2005; 226, 378-382 15. Hewson CJ, Luescher UA, Parent JM, et al. Efficacy of clomipramine in the treatment of canine compulsive disorder. J Am Vet Med Assoc, 1998; 213,1760-1765 16. Irimijami M, Luescher UA, Douglass G et al. 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In: Dodman NH, Shuster L, eds. Psychopharmacology of animal behavior disorders. Malden, Mass: Blackwell Science Inc, 1998;41–63 22. Crowell-Davis SL, Seibert LM, Sung W et al. Use of clomipramine, alprazolam and behavior modification for the treatment of storm phobias in dogs. J Am Vet Med Assoc 2003;222,:744-8. 23. Gruen M, Sherman B. Use of trazodone as an adjunctive agent in the treatment of canine anxiety disorders; 56 cases (1995-2007). J Am Vet Med Assoc 2008: 233, 1902-1907 24. Herron M, Shofer FS, Reisner IR. Restrospective evaluation of the effects of diazepam in dogs with anxiety-related behaviour problems. J Am Vet Med Assoc 2008;233:1420–4 25. Ibanez M, Anzola B. Use of fluoxetine, diazepam and behaviour modification as treatment for anxiety related behavior disorders in dogs. J Vet Behav 2009; 4, 223-229 26. Takeuchi Y, Houpt KA, Scarlett JM. Evaluation of treatments for separation anxiety in dogs. J Am 27. Virga V, Houpt KA, Scarlett JM. 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J Am Vet Med Assoc 2009, 235, 1442-1449 39. Carter GR. Carbamazepine for the treatment of canine aggression; seven case studies. ACVB/AVSAB Proceedings, 2008, New Orleans, 50 40. Hart BL. Objectionable urine spraying and urine marking in cats; evaluation of progestin treatment in gonadectomized males and females. J Am Vet Med Assoc 1980;177, 529-533 41. Pageat P, Lafont C, Falewee C, et al. An evaluation of serum prolactin in anxious dogs and response to treatment with selegiline or fluoxetine. Appl Anim Behav Ssci 2007; 105, 342-350 42. Schneider B, Dodman NH, Maranda L. Use of memantine in treatment of canine compulsive 43. Wald R, Dodman N, Shuster L. The combined effects of memantine and fluoxetine on an animal model of obsessive-compulsive disorder. Exp Clin Psychopharmacol 2009: 17; 191-7 44. Dodman NH, Shuster L, Nesbitt G et al. The use of dextromethorphan to treat repetitive self-directed, scratching, biting or chewing in dogs with allergic dermatitis. 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