Drugs and natural therapeutics an evidence based approach (Proceedings)

Psychotropic drugs and natural alternatives might be used to help reduce the signs associated with phobic, panic or chronic anxiety states and to improve trainability especially in situations where the pet is too anxious, fearful or impulsive to control its responses. However, drugs can serve to reduce the underlying anxiety, they do not in themselves change the relationship with the stimulus so that concurrent behavior modification will also be needed to desensitize, countercondition and train desirable responses in the presence of the stimulus. Drugs may also be useful for feline urine marking and as an adjunct to therapy in some cases of aggression. There may also be some pathologic disorders affecting behavior, such as compulsive disorders where drugs might be necessary.

Evidence based decision making is a means of providing the best information and treatment options that evidence has to offer. The validity of the information, the fundamentals of all clinical trials and their trial design and the application of statistics is necessary to properly appraise the evidence. Treatment should be selected using the evidence combined with the clinician's expertise as to the patient, client and problem. In veterinary medicine there is limited availability to the process. Many sources of veterinary information fall in the poorest (D) level including personal experience, colleague opinion, text books, continuing education notes, internet or inconclusive studies. Studies based on in vitro research or from another species also fall into this category. The most desirable evidence (A) is from systematic reviews with homogeneity or randomized controlled clinical trials (RT). Where the assessment of multiple RT's is not possible, then a single RT with high confidence would be the next best option.

In veterinary behavior, much of the information has been extrapolated from human literature; however, drug metabolism and receptor effects vary between species which can lead to inaccurate assumptions with respect to dose, duration of effect, contraindications and side effects. Those few drugs that are licensed for use in pets should first be considered since there is published data with respect to safety, efficacy, side effects, contraindications, toxicity and pharmacokinetics. In addition, the technical support available from the manufacturer provides additional expertise, especially in the event of adverse events. Psychotropic drugs should be used with informed consent for any off-label use. A physical examination and blood and urine tests should be part of the minimum database prior to dispensing drugs and with continued use. Treatment options for cognitive dysfunction are discussed in a separate seminar.

Antidepressants

Antidepressants cause little or no sedation and are unlikely to inhibit learning or memory. They might help to control anxiety and panic and may decrease the intensity of outbursts. There is extensive evidence on the efficacy of clomipramine and fluoxetine in dogs for anxiety disorders including separation anxiety, compulsive disorders and phobias, and for the treatment of compulsive disorders and urine marking in cats. Selective serotonin reuptake inhibitors (SSRI) such as fluoxetine may also be indicated as an adjunct for the treatment of some forms of aggression including those with anxiety and impulse dyscontrol. Clomipramine and fluoxetine are licensed in the United States for the treatment of separation anxiety in dogs, and clomipramine is also licensed in other countries for separation anxiety, compulsive and anxiety disorders in dogs, and for urine marking in cats.

While antidepressants may achieve peak plasma levels within hours, this does not reflect their therapeutic effect since reuptake inhibition may induce down-regulation of postsynaptic receptors that are responsible for the clinical effects. Therefore, 4 to 8 weeks of therapy is generally recommended to fully assess therapeutic effects. Pheromones and benzodiazepines might be used concurrently at the outset if more immediate anxiolytic effects are needed. Tricyclic antidepressants (TCA) and SSRI's should not be used concurrently with other antidepressants or MAO inhibitors such as selegiline and amitraz and should be used cautiously in pets with seizures. Since SSRI's inhibit cytochrome P-450 enzymes, they can lead to increased toxicity when combined with drugs that are metabolized by these enzymes.

In dogs, when antidepressants are combined with behavior modification, a faster and greater improvement can be achieved in the treatment of separation anxiety.1-4 However, in one study behavior modification alone appeared to be as effective.Participants in this study reported that clomipramine reduced general activity and provided a modest suppression of attachment-related tendency to seek physical contact. In one recent study where the use of fluoxetine chewable tablets were compared to placebo without concurrent behavior modification, a drug effect was established;7 however even greater improvement was seen when fluoxetine was combined with a behavior modification plan (BMP).

i) Tricyclic antidepressants

The primary mechanism of action of TCA's such as clomipramine and amitriptyline is to block the reuptake of serotonin and to a lesser extent noradrenaline. The degree of serotonin and noradrenaline reuptake blockade, as well as anticholinergic, antihistaminic and alpha adrenergic effects varies between TCA's. While doxepin, imipramine, and amitriptyline have all been used in veterinary behavior, there is little evidence of their efficacy in pets. A few retrospective studies have been published on the use of amitriptyline in dogs, with approximately 50% of separation anxiety cases showing some improvement.6 No significant improvement was seen in canine aggression. In a retrospective study of compulsive disorders in dogs and cats, clomipramine was significantly more efficacious than amitriptyline.

Clomipramine is the most selective inhibitor of serotonin reuptake of the TCA's. It also inhibits noradrenaline reuptake and has mild anticholinergic and antihistaminic effects, which might account for some its side effects, such as transient reports of lethargy, dry mouth or gastrointestinal upset. TCA's are contraindicated with cardiac disease, glaucoma, or where urine retention is a concern, However, clomipramine is associated with less urinary stasis, cardiac disease and anticholinergic effects in dogs compared to humans, perhaps because of its shorter half life and rapid elimination.10 Clomipramine and its active intermediate metabolite desmethylclomipramine reach peak concentrations in less than 2 hours.10 In addition the ratio of clomipramine to desmethylclomipramine (which is responsible for most noradrenergic and anticholinergic side effects) is (3:1) in humans compared to dogs (1:2.5). At therapeutic doses, clomipramine and amitriptyline do not alter cardiac rate or rhythm.

Clomipramine in combination with a BMP is an effective treatment for separation anxiety. After one week, 47% of dogs receiving clomipramine plus BMP improved compared to 29% of the dogs receiving BMP alone. After 4 weeks the improvement with clomipramine plus BMP reached 63% and this trend continued through 8 weeks of treatment.3 More dogs were improved in the clomipramine group than the placebo group for destructiveness, urination and defecation. In a follow up of 76 cases, 12 dogs had been on treatment for over 13 months with no adverse effects or relapse, and 10 of the dogs showed further improvement. Of 22 dogs with complete resolution, 13.6% relapsed when the drug was ceased. Therefore, some dogs will require a longer course of drug therapy. Clomipramine, in combination with BMP has also been used for the treatment of storm phobias in combination with as needed benzodiazepines.13 Clomipramine is also effective for compulsive and anxiety disorders in dogs and cats, and feline urine marking. Urine retention may be a concern at higher doses.

ii) Selective serotonin reuptake inhibitors

SSRI's are selective in their blockade of the reuptake of 5HT1A into the presynaptic neurons. Because they are selective inhibitors of serotonin reuptake they may have fewer side effects than TCA's, including less cardiac effects and hypotension.21 They may also be preferable in pets where urine retention, increased intraocular pressure, sedation or anticholinergic effects might be a concern. Paroxetine does have mild anticholinergic effects. In dogs, SSRI's are most often used for the treatment of separation anxiety and compulsive disorders, as well as for the treatment of phobias, fear and anxiety induced aggression and for impulse control disorders.

Studies indicate that fluoxetine has a T max of 1.8 hours for fluoxetine and 12 hours for its active intermediate metabolite norfluoxetine and reaches a steady state in approximately 10 days. Since the clearance half life of fluoxetine is 6.2 hours and 49 hours for norfluoxetine gradual weaning is not required after 8 weeks of treatment. However, when the drug is used for longer than 8 weeks, it might be prudent to consider a gradual weaning to determine the lowest effective dose and to minimize potential withdrawal effects. In the clinical trial, after 8 weeks 73% of fluoxetine chewable tablets (FCT) + BMP treated dogs were improved in their overall severity scores compared with 51% of dogs treated with placebo + BMP. After the first week 42% of the FCT + BMP dogs were improved compared to 18% in the placebo + BMP group. Calmness, lethargy and anorexia were the most common side effects. If anorexia or weight loss is significant, the dose may need to be reduced. In a second multi-center 6 week trial of dogs with separation anxiety, the efficacy of FCT was compared to placebo without BMP to determine if there was an effect of drug alone. Overall severity scores were improved over the placebo group at all weeks with significant improvement at weeks 1 and 4.7 Although there was a significant drug effect, greater improvement was achieved using the combination of fluoxetine + BMP.

In a study of generalized anxiety disorders fluoxetine and paroxetine in combination with behavior modification were effective,22 and fluoxetine has been be useful in some forms of canine aggression.23 Fluoxetine has also been effective in the treatment of compulsive disorders in dogs, as has sertraline.16 Fluoxetine may also be effective in the treatment of feline urine marking.

Anxiolytics

i) Buspirone, an azapirone, is a serotonin (5HT1A) receptor agonist and also acts as a dopamine (D2) agonist. Buspirone has been used for mild forms of fear and anxiety with some data to support its use in urine marking cats. It is non-sedating, does not stimulate appetite, and does not appear to inhibit memory. It takes a week or more to reach effect and is therefore not useful for situational anxieties.

Both buspirone and benzodiazepines may be associated with aggression due to disinhibition

ii) Benzodiazepines potentiate the effects of (GABA), an inhibitory neurotransmitter. In general they cause decreased anxiety, hyperphagia, muscle relaxation and decreased locomotor activity. They reach peak effect shortly after each dose and can therefore be used alone, or in combination with other drugs on an as needed basis. Since clonazepam, oxazepam and lorazepam have no active intermediate metabolites, they may be safer for pets with compromised hepatic function. Benzodiazepines need to be dosed frequently and there may be a rebound effect if withdrawal is not gradual. They can cause paradoxical excitability and can have an amnesic effect. Benzodiazepines are useful for counterconditioning since they decrease anxiety and increase appetite. They can also be used for drug desensitization where the dose is gradually reduced after each successful and positive exposure. Diazepam may be effective for urine marking in cats. However, liver function should be monitored prior to and during therapy as rare cases of hepatotoxicity and death have been reported in cats.

iii) Beta blockers such as propranolol have been used to reduce the physiologic signs of anxiety in combination with drugs that diminish behavioral signs. By blocking beta adrenergic activity, physical signs of anxiety (rapid heart rate, increased respiratory rate, muscle tremors, palpitations, gastrointestinal upset, sweating, trembling) are decreased. Without these signals, the fear response may be diminished.

Neuroleptics decrease motor function at the level of the basal ganglia in the brain, elevate prolactin levels and may reduce aggression through their action as dopamine antagonists. Phenothiazines such as acepromazine are used for their sedating effects but do not reduce anxiety. They are anticholinergic and should not be used in patients with seizures, liver disease or heart problems.

Progestins (medroxyprogesterone or megestrol acetate) have been used for a wide range of behavior problems in dogs and cats ranging from aggression to feline urine marking. They may have a calming affect but appear to be most effective in treating androgen induced behaviors. However since they have the potential for causing gynecomastia, mammary tumors, adrenocortical and bone marrow suppression, acromegaly and diabetes, they are generally only used as a last resort.

Selegiline is an MAOB inhibitor which enhances catecholamine transmission. It is licensed in North America for the treatment of CDS and in Europe for use in association with behavior therapy for the treatment of emotional disorders. A recent study identified higher prolactin levels in dogs with chronic stress and high anxiety associated with stereotypic and displacement behaviors, fear aggression and autonomic signs. Lower levels of prolactin were associated with fear and mild phobias. Selegiline was significantly more effective in the treatment of dogs with high prolactin while fluoxetine was significantly more effective in dogs with low prolactin. In a study of 4 dogs with social and sound phobias, a behavior modification program plus selegiline in conjunction with propranolol and alprazolam as needed, was effective. In a study in which selegiline was compared to alpha-casozepine, both products led to significantly improved emotional disorder scores (EDED) and owner assessment scores of anxiety disorders of dogs. In a placebo trial, dogs given selegiline performed better at lure reward tasks, were significantly more likely to walk across a novel object on the floor and were less distracted.

Dosing and compliance

Since many owners cannot administer medications, they are being reformulated into compounded liquids, flavored tablets and transdermal medications. For compounded medications, it is necessary to determine the stability and storage of these products. To date, there has been no data to support the efficacy of transdermal medication for behavior drugs in cats. One study found that the bioavailability of transdermal doses of fluoxetine was 10% compared to oral dosing. In another study comparing plasma concentrations after a single oral dose to transdermal administration, systemic absorption of both amitriptyline and buspirone was poor compared to the oral route.36

Natural products and supplements

"Natural" products can have great variation in quality, level of activity, and efficacy. Adverse effects, toxicity and contraindications have yet to be established and there are very few efficacy studies:

a) Pheromones bind to pheromone binding proteins that are specific to that species. This activates receptors which alter the pet's emotional state or activates physiologic effects such as hormone release.

i) The feline cheek gland pheromone (F3) known is deposited by the cat throughout the environment by facial rubbing. It serves to mark out boundaries and provide emotional stability perhaps by indicating known objects from unknown. Synthetic F3 pheromone may be effective in reducing marking and scratching, anxiety during car transportation and when introducing cats to new environments.

ii) DAP is a synthetic version of the intermammary appeasing pheromone in the lactating bitch. Its function is to calm and reassure the offspring. The DAP diffuser has been effective in helping puppies adapt to a new home, in reducing arousal and increasing appeasement behavior in puppy classes, in reducing anxiety in veterinary clinics and shelters, and for fear of fireworks (in conjunction with CD desensitization). The DAP diffuser plus BMP was compared to clomipramine plus BMP in a 28 day placebo trial. Behaviors improved in both groups with no significant difference in overall improvement between the two groups.12 The DAP spray and collar were both effective in improving car travel especially physical or autonomic signs. The collar has also been shown to reduce fear and anxiety and improve learning and owner satisfaction in puppy classes compared to placebo.49 In another placebo study of newly adopted puppies there was significantly less nuisance behaviors and a reduction in fear and distress over the first two weeks.0

) Melatonin is derivative of serotonin and may inhibit dopamine. Melatonin has been reported to be useful as a sleep aid and for canine fears and phobias at .1 mg/kg tid. In one case study melatonin was used successfully when combined with amitriptyline on an as needed basis for noise phobias.

c) Diet / Tryptophan - In one canine study, the level of protein in the diet or addition of l-tryptophan had no effect on fearfulness or hyperactivity. However, reduced protein diets with tryptophan supplementation were shown to lower territoriality scores while high protein diets without tryptophan were associated with greater dominance aggression.

d) Alpha-casozepine is a hydrolyzate of a protein in cow's milk. In one study it was equally effective as selegiline in improving EDED scores and in the reducing anxiety in dogs. In a study of 34 cats, alpha-casozepine significantly improved fear of strangers, contact with familiars, general fear, fear related aggression and autonomic signs compared to placebo.

e) In a study of 5 dogs using l-theanine plus a CD desensitization for noise phobia there was a statistical improvement in signs and greater owner improvement than in a placebo group.. In a study of 32 cats with signs of anxiety (e.g. inappropriate elimination, fear aggression, physical signs) there was improvement in all signs, especially the organic manifestations.

f) Other natural, nutraceutical and herbal compounds for which there is no published data include St. John's Wort, DHA, Eleutherococcus (Siberian ginseng) to improve mental acuity; Panax ginseng as a stimulant; Passionflower (Passiflora), skullcap for anxiety; hops for insomnia, homeopathy, flower remedies and acupuncture. Aromatherapy may have some efficacy in reducing travel anxiety.

References available on request