7 Leticia Mattos de Souza Dantas and Sharon L. Crowell‐Davis University of Georgia, Athens, GA, USA The benzodiazepines work by facilitating GABA in the central nervous system (CNS). They do this specifically by binding to GABAA receptors. The behavioral effects are due to action on the hypothalamus and the limbic system. Benzodiazepines are anxiolytic medications with a rapid onset of action that lasts for a few to several hours, depending on the specific drug and the species. There are specific binding sites in the brain for benzodiazepines, with the highest density being in the central cortex, the cerebellum, and the limbic system (Braestrup and Squires 1977; Möhler and Okada 1977; Danneberg and Weber 1983). There are benzodiazepine receptors elsewhere in the body, for example, on bovine adrenal chromaffin cells (Brennan and Littleton 1991). Thousands of benzodiazepine molecules have been synthesized, although only a small segment of these are available commercially (Sternbach 1973). While thousands of papers have been published on laboratory studies of the effects of benzodiazepines on nonhuman animals and the clinical studies of their effect on humans, few clinical studies or even case reports of their effect on nonhuman animals have been published. Fortunately, there are a few, and some of the laboratory studies conducted on animals provide useful information on such topics as toxicity, half‐life and dose–response relationships. Of the commercially available benzodiazepines, only alprazolam, chlordiazepoxide, clonazepam, clorazepate dipotassium, diazepam, flurazepam, lorazepam, oxazepam, and triazolam will be discussed in this chapter. Benzodiazepines are potentially useful for any problems involving anxiety, fear, or phobia in which a rapid onset of action is desired. Their immediate and discrete efficacy makes them particularly useful for fears that are induced by specific stimuli that can be predicted in advance. Examples of appropriate use include fear‐based urination, urine marking, or specific phobias such as storm phobia or separation anxiety with panic, and fear of people (without aggression) in dogs; feather‐picking and fear of people in birds; foal rejection due to fear in mares; urine marking, storm phobia, separation anxiety, and fear/anxiety in cats. In humans, benzodiazepines reduce somatic symptoms of generalized anxiety disorder, but do not reduce cognitive symptoms, that is, chronic worry (Gorman 2003). Thus, they are probably not an ideal drug of choice for veterinary patients that exhibit chronic anxiety independent of external stimuli. Benzodiazepines with active metabolites, especially diazepam, should be used with caution in cats because of the rare possibility of medication‐induced hepatic necrosis. The use of benzodiazepines in cases involving aggression is controversial. When chlordiazepoxide and diazepam were first released in the early 1960s for use in psychiatry, they were considered to have great potential in the treatment of aggression in humans because in various studies of laboratory animals it was noted that they had an effect of calming and taming “wild” or “vicious” animals (DiMascio 1973). However, the potential initially believed to be present did not turn out to be either consistent or reliable. Effect on aggression varies between species and between individuals and depends on the type of aggression being measured and how it is provoked, the specific benzodiazepine, the specific dose, and whether or not the benzodiazepine is given as a single, acute dose or whether it is given repeatedly over a period of days (see Randall 1960, 1961; Boyle and Tobin 1961; Heise and Boff 1961; Heuschele 1961; Horowitz et al. 1963; Scheckel and Boff 1966; Valzelli et al. 1967; Boissier et al. 1968; Fox and Snyder 1969; Hoffmeister and Wuttke 1969; Sofia 1969; Bauen and Possanza 1970; Christmas and Maxwell 1970; Cole and Wolf 1970; Fox et al. 1970; Guaitani et al. 1971; Langfeldt and Ursin 1971; Miczek 1974; Salzman et al. 1974; Kochansky et al. 1975; Miczek and O’Donnell 1980; Rodgers and Waters 1985; Mos et al. 1987; Mos and Olivier 1989; Olivier et al. 1991; Gao and Cutler 1993; Miczek et al. 1995; Tornatzky and Miczek 1995 for some examples of research on humans and animals that repeatedly identify these discrepancies). While benzodiazepines sometimes decrease aggressiveness, their use sometimes results in increased aggression. Relief from anxiety can result in the loss of inhibition of behavior (e.g. Margules and Stein 1968). This results in modern textbooks of veterinary behavior being ambivalent on the subject of the use of benzodiazepines in the treatment of nonhuman aggression. For example, Landsberg et al. (2003) state: “Benzodiazepines can be considered for the treatment of any condition that may have a fear or anxiety component, including fear aggression …,” but later in the same paragraph they point out that benzodiazepine’s “disinhibition could lead to an increase in aggression.” In more recent publications, caution is still advised (Horwitz and Neilson 2007; Landsberg et al. 2013). Clinically, just as alcohol or benzodiazepines can result in loss of inhibitions and consequent atypical behavior, including aggression, in humans, so can the use of benzodiazepines result in loss of normal inhibitions and consequent atypical behavior in animals. The challenge is distinguishing between inhibited and un‐inhibited behaviors, since an animal that is already showing aggression, in theory, is not inhibited. However, that does not mean that the aggressive behavior could not further escalate. In addition, benzodiazepines, particularly diazepam, appear to increase impulsivity (Thiébot et al. 1985), which is a component that, when present in aggressive behavior, is a poor prognostic indicator for nonhuman patients. Generally, lacking good clinical guidelines as to the specific aggression situations in which benzodiazepines might be helpful or risky, they should be avoided or used with extreme caution in cases involving aggressive animals. It is essential that companion animal owners are educated about the potential risks. The benzodiazepines may result in increases in affiliative behavior. For example, rhesus monkeys (Macaca mulatta) treated with chloridazepoxide, diazepam, or lorazepam exhibit increased social grooming, social approach, and social contact (Kumar et al. 1999). All benzodiazepines are metabolized in the liver and excreted through the kidneys. Therefore, premedication blood work to assess the function of these organs is recommended. Side effects include sedation, ataxia, muscle relaxation, increased appetite, paradoxical excitation, increased friendliness, anxiety, hallucinations, muscle spasticity, insomnia, and idiopathic hepatic necrosis in cats. The latter has specifically been reported as a response to diazepam. Treatment of overdose is primarily supportive. Activated charcoal can be used to adsorb benzodiazepines within the gastrointestinal tract. In cats, vomiting can be induced with 0.05 mg kg−1 of apomorphine subcutaneously (SC) or 1 mg kg−1 xylazine SC. Flumazenil (Mazicon), a benzodiazepine receptor antagonist, can be given to partially or fully reverse the effects. Typically administered intravenously in veterinary medicine, a study with dogs as an animal model for children showed that the intralingual and submucosal routes can be viable alternatives for reversing benzodiazepine sedation (Unkel et al. 2006). That warrants further investigation in companion animals as these options could be practical for hypotensive and hypovolemic patients. Three hours after ingestion, gastric lavage or induction of vomiting is not recommended, because benzodiazepines are rapidly absorbed from the gastrointestinal tract. By this time, gastric lavage or induction of vomiting is not useful and sedation or convulsions will make these procedures counterproductive. Hypothermic patients should be kept in a warm environment. Intravenous fluids can help increase the rate of excretion of the benzodiazepine. In a study of benzodiazepine poisoning in companion animals, specifically dogs and cats, the 10 most common signs observed in dogs were, in order of prevalence, ataxia, prostration, agitation, vomiting, hyperesthesia, muscle tremors, coma, hypersalivation, aggressiveness, and paresis. In cats, the 10 most common signs were prostration, ataxia, muscle tremors, agitation, coma, mydriasis, polypnea, decubitus, bradypnea, and vomiting (Bertini et al. 1995). Several publications that are more recent have pointed out that the accidental ingestion of an owner’s benzodiazepines is common, and highlights the need of veterinarians to discuss safety measures with clients (Campbell and Chapman 2000; Gusson et al. 2002; Wismer 2002; Cope et al. 2006; Cortinovis et al. 2015). Benzodiazepines are DEA Schedule IV drugs. While they are available by prescription, there is potential for human abuse due to both psychological and physical dependency. Benzodiazepines are excreted through the milk and pass through the placenta. They therefore should be used with caution and generally avoided in pregnant or lactating females. While benzodiazepines are good anxiolytics, they can have an amnesic effect and sometimes interfere with learning. Thus, they may be more useful in situations in which the control of intense fear is more important than ongoing learning. Nevertheless, the fact that they can have an amnesic effect does not mean that they always do, and research on the ability to learn while under the influence of benzodiazepines exhibits as much variation as research on the effect of benzodiazepines on aggression (e.g. Iwasaki et al. 1976; Vachon et al. 1984; Hodges and Green 1987). The authors have had numerous cases in which learning that was subsequently retained long term clearly occurred while the patient was given a benzodiazepine. The potential deleterious effects of benzodiazepines for human patients with cognitive impairment and dementia disorders (such as Alzheimer’s disease) have been under investigation. Accelerated cognitive deterioration has been reported (Billioti de Gage et al. 2012; Billioti de Gage et al. 2015; Defranchesco et al. 2015; Pariente et al. 2016). Such studies raise a concern regarding the prescription and long‐term treatment of senior and elderly veterinary patients, even though similar investigations have not been carried out in veterinary medicine yet. Benzodiazepines have also been associated with falls in elderly people (Pariente et al. 2008; Ballokova et al. 2014) and increased mortality with long‐term use (Charlson et al. 2009). The use of benzodiazepines for sedation of patients with post‐traumatic stress disorder has been associated with greater post‐intensive care symptoms (Parker et al. 2015). There is wide variation in the optimum dose for a given patient. It is best to have the client give the pet a test dose in the low range of the dosage schedule at a time when they will be home to watch the pet for several hours. It is also necessary to give clients safety instructions due to the potential of benzodiazepines causing ataxia and incoordination (e.g. blocking access to stairs and balconies), among other concerns such as hyperphagia. In this way they can observe whether their pet has such side effects as paradoxical excitement or sedation at that dose. Paradoxical excitement generally occurs at a specific window of dosage. Therefore, if paradoxical excitement occurs, the dose should be increased, while if sedation occurs, the dose should be decreased. If the patient exhibits no side effects, the medication can then be tried at that dose in the situation that induces fear. If the low dose used at the beginning is insufficient to alleviate the fear, steadily increase the dose until fear is alleviated or side effects are encountered. Withdrawal of patients that have been frequently dosed with benzodiazepines over a period of several weeks should be gradual. This allows the identification of a specific dose that may still be required to control the problem behavior. Also, sudden termination in a patient that has been continuously on a benzodiazepine for several weeks can result in rebound, that is, a resumption of symptoms that may be more intense than they were before treatment. While specific schedules for decreasing medication will vary with the patient, a general rule is to decrease no faster than 25–33% per week. Many patients will require that the decrease occur more slowly. In addition to the above considerations, all benzodiazepines have the potential to produce physical addiction. Generally, benzodiazepine dependency in human medicine is associated with high dosage drug regimens, use of benzodiazepines of higher potency and short duration of action, and with long duration of treatment (Riss et al. 2008; Brett and Murnion 2015). However, investigation of these factors is lacking in veterinary medicine and ignores the role of genetics and other physiological factors in physiological tolerance. Different benzodiazepines produce different kinds of physical dependence. In studies of flumazenil‐induced abstinence in dogs that had been treated chronically with diazepam, nordiazepam, flunitrazepam, alprazolam, oxazepam, halazepam, and lorazepam, it was found that oxazepam and lorazepam resulted in a less‐intense physical dependence than did the other benzodiazepines (Martin et al. 1990). Therefore, if it is anticipated that a dog will need to be regularly medicated with a benzodiazepine for an extended period of time, oxazepam or lorazepam may be a better choice than the other benzodiazepines. Dogs made dependent on diazepam by prolonged administration of 60 mg kg−1 day−1 and acutely withdrawn by administration of flumazenil exhibit tremor, rigidity, decreased food intake, and tonic, clonic convulsions (McNicholas et al. 1983). Tolerance is a phenomenon that also occurs with these medications; that is, when a patient is on a benzodiazepine for an extended period, steadily greater doses may be required to achieve the same behavioral effect (Danneberg and Weber 1983). Benzodiazepines can safely be used with a variety of other psychoactive medications. Details of these combinations are discussed further in Chapter 19. The doses of the various benzodiazepines are shown in Tables 7.1 and 7.2. Table 7.1 Doses of various benzodiazepines for dogs and cats. Source: Scherkl et al. (1985), Dodman and Shuster (1994), Simpson and Simpson (1996), Overall (1994b, 1997, 2004), Simpson (2002), Crowell‐Davis et al. (2003), Landsberg et al. (2003). Note: All doses given are orally and are given as needed until the desired effect is reached. The hourly schedules are the maximum frequency at which the medication should be given. As a general rule, start at the lowest dose and titrate upward if needed. See text for further explanation. Alprazolam is readily absorbed following oral administration. In humans, peak concentrations occur in the plasma at one to two hours, and the plasma levels are proportionate to the dose given. Mean plasma elimination half‐life in healthy humans is about 11.2 hours. However, in humans, changes in absorption, distribution, metabolism, and excretion occur in various disease states; for example, impaired hepatic or renal function. This is no doubt also the case in nonhuman animals. Doses should be decreased in old or obese veterinary patients and in those with impaired liver or renal function (Pharmacia and Upjohn 2001). The two most common metabolites are α‐hydroxy‐alprazolam and a benzophenone. The benzophenone is inactive, but α‐hydroxy‐alprazolam has about half the activity of alprazolam. Metabolism is initiated by hydroxylation that is catalyzed by cytochrome P450 3A. Therefore, any drugs that inhibit the activity of this metabolic pathway are likely to result in decreased clearance of alprazolam (Pharmacia and Upjohn 2001). In humans, extended‐release tablets are absorbed more slowly than non‐extended‐release tablets, resulting in steady‐state concentration that is maintained for 5–11 hours after dosing. Time of day, consumption of a meal, and type of meal affect the absorption rate (Pharmacia and Upjohn 2001). Since the digestive physiology and typical diet of veterinary patients differ significantly from the digestive physiology and diet of humans, it is likely that there is substantial variation from the human data. In African green monkeys, the mean elimination half‐life is 5.7 hours (Friedman et al. 1991). In humans, alprazolam is approved for use in generalized anxiety disorder, anxiety with depression, and panic disorder with or without agoraphobia. Effective treatment of panic disorder requires several months, and withdrawal must be very gradual, taking at least eight weeks, in order to avoid rebound (Pecknold et al. 1988). Alprazolam is contraindicated in patients with known hypersensitivity to benzodiazepines, glaucoma, or severe liver or kidney disease. It is also contraindicated in pregnant or lactating females. It should not be given with medications that significantly impair the oxidative metabolism of cytochrome P450 3A, such as the antifungal agents ketoconazole or itraconazole (Pharmacia and Upjohn 2001). Side effects typical of the benzodiazepines, including sedation, ataxia, muscle relaxation, increased appetite, paradoxical excitation, and increased friendliness, may occur. Rats treated with 3–30 mg kg−1 day−1 of alprazolam over a two‐year period showed a dose‐related tendency to develop cataracts in females and corneal vascularization in males. Lesions appeared after at least 11 months of treatment. Rats given doses of alprazolam up to 30 mg kg−1 day−1 and mice given doses up to 10 mg kg−1 day−1 for a period of two years showed no evidence of increased cancer. Alprazolam has not been shown to be mutagenic in rats. In rats given alprazolam at doses up to 5 mg kg−1 day−1, fertility was unimpaired. The LD50 (the dose that kills half of the animals tested) in the rat is 331–2171 mg kg−1 (Pharmacia and Upjohn 2001). Clinical signs reported in dogs that had consumed overdoses of up to 5.55 mg kg−1 alprazolam included ataxia, disorientation, depression, hyperactivity, vomiting, weakness, tremors, vocalization, tachycardia, tachypnea, hypothermia, diarrhea, and increased salivation. In 38% of the cases, clinical signs developed within 30 minutes of ingestion. Ataxia typically resolved within 9 hours, but some dogs were ataxic for up to 24 hours. Depression lasted 10–31 hours. There was no correlation between the dose consumed and paradoxical excitement (Wismer 2002). Treat an overdose with gastric lavage and supportive treatment, including fluids. Flumazenil may be given for complete or partial reversal; however, administration of flumazenil to a patient that has received alprazolam daily for several weeks may result in convulsions. Initiate treatment at the lowest dose. If no undesirable side effects occur, titrate dose up to the desired effect. If a patient has been receiving alprazolam daily for several weeks, discontinuation should be gradual, and conducted over a period of at least one month. While liver failure has not been reported in cats or other veterinary patients given alprazolam for behavior problems, it has occurred in humans. While it is a rare event even in humans, liver failure should always be considered as a possible sequela to medication with alprazolam. Dogs given alprazolam at an escalating dose over 18–26 days until a dose of 12 mg kg−1 four times a day (q.i.d.) is attained, then maintained on that dose for about three weeks, become physically addicted, as demonstrated by flumazenil‐precipitated abstinence (Sloan et al. 1990). These doses are much higher than would be given for the clinical treatment of anxiety disorders. Acute withdrawal of an addicted dog may result in seizures. Other sequelae to withdrawal reported in humans include insomnia, abnormal involuntary movement, headaches, muscle twitching, and anxiety. Dogs addicted to alprazolam that underwent acute withdrawal due to administration of flumazenil exhibited wild running, barking, and lunging at nonexistent objects, and uncontrolled splaying, rigidity, and jerking of the limbs (Martin et al. 1990). As with humans, veterinary patients that have been on alprazolam daily for several weeks should have their dose gradually decreased. As with other benzodiazepines, alprazolam is particularly noted for its rapid action. For example, in the treatment of humans with panic disorder, patients treated with alprazolam respond within the first week of treatment, while patients treated with imipramine, a tricyclic antidepressant, respond, but not until the fourth week of treatment (Charney et al. 1986). This rapid response has been observed clinically in veterinary patients, making alprazolam a good choice for dogs that exhibit panic behaviors to the degree that rapid improvement is essential. While the use of alprazolam to treat behavior problems in cats is mentioned in several textbooks, the authors are unaware of any papers presenting results of clinical use in this species with the exception of a report on humane handling of cats in the veterinary hospital. Anseeuw et al. (2006) suggested using alprazolam to decrease arousal in cats returning home from medical visits, especially if their housemates become reactive upon the reunion. Crowell‐Davis et al. (2003) used alprazolam as part of a treatment protocol for dogs with storm phobia. Alprazolam is most likely to be effective if it is given 30–60 minutes before the occurrence of the earliest stimuli that elicit fear responses, for example, the sound of rain or strong winds. To do this, owners of storm‐phobic pets must monitor weather conditions closely. As a general rule for patients with severe signs of this phobia, medication should be given if there is any likelihood that weather conditions that induce fear responses will occur. If, however, the fear‐inducing stimuli have already begun and the patient is showing fear when the owner realizes there will be a problem, alprazolam should still be administered. For alprazolam‐responsive patients, fear is likely to be somewhat abated, although a higher dose may be required for full relief from signs of fear. In a case report published by Duxbury (2006), alprazolam was used as an adjunctive medication to a treatment protocol with clomipramine to control anxiety signs during the owner’s absence in a dog diagnosed with separation anxiety disorder. Alprazolam was administered orally one hour before departures. Dogs chronically dosed with increasing quantities of alprazolam until they began losing weight did so at doses of 48 mg kg−1 by day 18–28 of the increasing regimen (Martin et al. 1990). Chlordiazepoxide HCl acts on the limbic system of the brain, modifying emotional responses. It has antianxiety, appetite‐stimulating, and sedative effects. It is also a weak analgesic. It does not have an autonomic blocking effect, so moderate doses do not affect blood pressure or heart rate (Randall et al. 1960). It crosses the blood–brain barrier, is highly bound to plasma proteins, and is metabolized by the liver. Metabolites generated in the liver include desmethyldiazepam (nordiazepam), demoxepam, desmethylchlordiazepoxide, and oxazepam (Schwartz and Postma 1966; Kaplan et al. 1970; ICN Pharmaceuticals 1996). These metabolites are active and typically have long half‐lives. In humans, peak blood levels are not reached until several hours after taking the medication. Chlordiazepoxide has a half‐life in humans of 24–48 hours, and plasma levels decline slowly over several days. Chlordiazepoxide is excreted in the urine, with only 1–2% in unchanged form (ICN Pharmaceuticals 1996). In dogs, plasma levels peak around 7–8 hours after a single dose of 4 mg kg−1 or 20 mg kg−1 of chlordiazepoxide. Plasma levels are about half the peak value after 24 hours and chlordiazepoxide is still being excreted in the urine 96 hours after administration. This dose causes mild sedation with high plasma levels for 24 hours in this species. When dogs are redosed daily, there is no cumulative effect on blood levels or sedation. Dogs given doses of 50 mg kg−1 by mouth (PO) for six months have shown no adverse effects (Randall 1961). Doses of 10–40 mg kg−1 may produce ataxia, while doses of 80 mg kg−1 produce sleep when dogs are not stimulated (Randall et al. 1960). Doses of 2.5–20 mg kg−1 have an appetite‐stimulating effect (Randall et al. 1960). When dogs are given a single dose of 0.5–0.8 mg kg−1 PO, peak plasma levels occur earlier, just two to five hours after dosing, and the half‐life is likewise shorter, 12–20 hours (Koechlin and D’Arconte 1963). Seven days after administration of a single dose of 4 mg kg−1, 44% of the dose is recovered through the urine, while five days after the same dose an additional 44% is recovered in the feces. Urinary excretion rate peaks at 10 hours after oral administration (Koechlin et al. 1965). In the dog, demoxepam, one of the metabolites of chlordiazepoxide, has a half‐life of 10–20 hours, with substantial individual variation. Some of the demoxepam is subsequently converted to oxazepam (Schwartz et al. 1971). Slightly over 1% (1.1%) of chlordiazepoxide given as a single 26 mg kg−1 dose PO or as a daily dose of 5 mg kg−1 PO for nine weeks is ultimately excreted in the urine as oxazepam, while an additional 1.3% is excreted in the feces on either regimen (Kimmel and Walkenstein 1967). Electroencephalographic studies in the cat have shown that the peak drug effect for chlordiazepoxide, when given at 1.25 mg kg−1 intraperitoneally (IP), occurs within 90 minutes (Fairchild et al. 1980). The LD50 in mice is 123 ± 12 mg kg−1 IV and 366 ± 7 mg kg−1 intramuscularly (IM). In rats, the LD50 is 120 ± 7 mg kg−1 IV and more than 160 mg kg−1 IM (ICN Pharmaceuticals 1996). The oral dose LD50 is 590 mg kg−1 in rabbits, 1315 mg kg−1 in rats, and 620 mg kg−1 in mice (Randall et al. 1965). In cats, a dose of 200 mg kg−1 PO was fatal in five days (Randall and Kappell 1973). Chlordiazepoxide is used in the treatment of various anxiety disorders, for short‐term relief of symptoms of anxiety, for example, preoperatively, and for relief from symptoms of alcoholism. Chlordiazepoxide is contraindicated in patients with known sensitivity to this or other benzodiazepines. Avoid or use with extreme caution in patients with a history of aggression, because chlordiazepoxide, like all benzodiazepines, may cause loss of learned inhibitions. Reduced doses should be used in geriatric patients and patients with mild to moderate liver or kidney disease. Chlordiazepoxide crosses the placental barrier and enters the milk. There is an increased risk of congenital malformations when chlordiazepoxide is given during the first trimester of pregnancy. Therefore, its use should be avoided in pregnant as well as lactating females. Various side effects, including sedation, ataxia, paradoxical excitation, and rage may occur. In humans, there have been isolated reports of effects on blood coagulation in patients receiving chlordiazepoxide at the same time that they are given anticoagulants. Blood dyscrasias, jaundice, and hepatic dysfunction occasionally occur in humans (ICN Pharmaceuticals 1996). Any veterinary patient that is maintained on chlordiazepoxide for an extended period of time should have complete blood counts and blood chemistries conducted regularly. Tolerance may develop, particularly to the sedative effects (Goldberg et al. 1967). Two out of six dogs given chlordiazepoxide at 127 mg kg−1 died with evidence of circulatory collapse, as did six out of six given 200 mg kg−1 day−1. Dogs given 80 mg kg−1 exhibited nonspecific toxic changes (Wyeth Laboratories Inc. 1999b). Rat pups of mothers given 10, 20, and 80 mg kg−1 during conception and pregnancy had normal growth and showed no congenital anomalies. Lactation of the mothers was unaffected. When rats were given 100 mg kg−1, there was a significant decrease in fertilization rate. There was also a decrease in the viability and body weight of the pups. These problems were attributed to the sedation induced at this dose, which resulted in less mating activity and decreased maternal care. Some of the offspring also exhibited skeletal defects at this dose (ICN Pharmaceuticals 1996). In case of overdose, conduct gastric lavage immediately, then provide general supportive therapy. Administer intravenous fluids and maintain an adequate airway. If excitation occurs, do not use barbiturates. Flumazenil is indicated for the complete or partial reversal of the sedative effects of chlordiazepoxide. Initiate treatment at the lowest dose. If no undesirable side effects occur, titrate dose up to the desired effect. As with other benzodiazepines, if the patient has been receiving chlordiazepoxide daily for several weeks, discontinuation should be gradual and conducted over at least a one‐month period of time. Chlordiazepoxide has been shown to cause delayed reversal learning and failure to accomplish successive discrimination learning in the rat, although it does not disrupt simultaneous discrimination (Iwahara and Sugimura 1970; Iwasaki et al. 1976). Taming effects have been noted in multiple species, including monkeys, rats, tigers, lions, dingos, and squirrels at doses that did not induce sedation (e.g. Harris 1960; Heise and Boff 1961; Scheckel and Boff 1966). Laboratory cats given chlordiazepoxide intraperitoneally at doses ranging from 1.25 to 5 mg kg−1 exhibited dose‐related stimulation and decreased sleep. They were also observed to be playful or mildly aggressive on this medication, although what form of aggression was exhibited is not specifically described (Fairchild et al. 1980). At 10 mg kg−1 PO, cats exhibit muscle relaxation when suspended by the scruff of the neck (Randall 1961). Angel et al. (1982) treated a strain of nervous pointer dogs with chlordiazepoxide or placebo at 3.5 mg kg−1 in the morning for seven consecutive days. The dogs’ avoidance of humans was significantly attenuated with the chlordiazepoxide treatment, but not the placebo. The dogs’ behavior returned to baseline four days after discontinuation of medication (Angel et al. 1982). Five of eight laboratory beagle dogs with abnormal withdrawn and depressed behavior exhibited improvement when given 5 mg kg−1 daily of chlordiazepoxide, while the behavior of all three of three beagles with the same symptoms, given 2.5 mg kg−1 daily of chlordiazepoxide, was resolved (Iorio et al. 1983). Chlordiazepoxide has an appetite stimulation effect in dogs, with a single low dose increasing food intake of fasted dogs. Chronic treatment with chlordiazepoxide for 90 days results in weight gain (Randall et al. 1960). Chlordiazepoxide has been used to tame monkeys at a dose of 1 mg kg−1 (Zbinden and Randall 1967). In social colonies of rhesus monkeys, chlordiazepoxide (2.5–5.0 mg kg−1 PO daily) produces dose‐dependent increases in social grooming, approach, contact, self‐grooming, feeding, and resting with the eyes open. There is also decreased vigilance and aggression (Kumar et al. 1999). A number of zoo animals changed from being aggressive or intensely frightened to being calm, nonaggressive, and even friendly when given chlordiazepoxide. These include a male European lynx (Lynx lynx; 6 mg kg−1 PO), a female dingo (Canis familiaris dingo; 3–7 mg kg−1 PO), a female Guinea baboon (Papio papio; 13 mg kg−1 PO), a male California sea lion (Zalophus californianus; 7 mg kg−1 PO), a male Burmese macaque (Macaca nemestrina andamensis; 5 mg kg−1 IM), a female red kangaroo (Macropus rufus; 11 mg kg−1 PO), a female mule deer (Odocoileus hemionus; 2.2 mg kg−1 IV), a male white‐bearded gnu (Connochaetes taurinus; 4 mg kg−1 IM), a female gerenuk (Litocranius walleri; 5 mg kg−1 IM), and three golden marmosets (Leontocebus rosalia; 15 mg kg−1 PO) (Heuschele 1961). Animals that did not respond as desired to chlordiazepoxide included a male klipspringer (Oreotragus oreotragus saltatrixoides), a female South American tapir (Tapirus terrestris), and a Hensel’s cat (Felis pardinoides) (Heuschele 1961). Clonazepam is completely and rapidly absorbed following oral dosing. In humans, maximum plasma concentrations are reached in one to four hours, with an elimination half‐life of 30–40 hours. Dogs given 0.2 mg kg−1 IV exhibit an elimination half‐life of 1.4 ± 0.3 hours. Most clonazepam is metabolized to various inactive metabolites. In humans, less than 2% is excreted in the urine in an unchanged form. Because extensive metabolism occurs in the liver, hepatic disease may result in impaired elimination. Thus, clonazepam is not the best choice for patients with liver disease. Pharmacokinetics are dose‐dependent throughout the dose range (Al‐Tahan et al. 1984, Roche Laboratories 2001). Cats given 1000 mg kg−1 clonazepam PO survived. In contrast, cats given bromazepam died at a dose of 1000 mg kg−1, while several benzodiazepines proved fatal in cats at much lower doses (Randall and Kappell 1973). In dogs given 0.5 mg kg−1 of clonazepam every 12 hours (q12h) for a period of three weeks, the elimination half‐life of clonazepam increases with each passing week. In week one, the average half‐life is about two hours, while by week three it is almost eight hours. Acute withdrawal from clonazepam after three or more weeks of treatment has been shown to result in anorexia, hyperthermia, and weight loss (Scherkl et al. 1985). Plasma concentrations in the range considered to be therapeutic in humans can be maintained in dogs by dosing 0.5 mg kg−1 two times a day (b.i.d.) or three times a day (t.i.d.) (Al‐Tahan et al. 1984). Clonazepam is used to treat a variety of seizure disorders and panic disorder. Clonazepam is contraindicated in patients with a history of sensitivity to benzodiazepines, severe liver or kidney disease, or glaucoma. Clonazepam should not be given to pregnant or lactating females. Low doses should be used in patients with mild to moderate kidney or liver disease, because their ability to metabolize and excrete clonazepam will be compromised. As with all benzodiazepines, clonazepam may result in sedation, ataxia, muscle relaxation, increased appetite, paradoxical excitation, increased friendliness, anxiety, and hallucinations. Carcinogenicity of clonazepam has not been studied. Genotoxic studies are insufficient to conclude if clonazepam has any genotoxic potential. In rats given 10–100 mg kg−1 day−1 over two generations, there was a decrease in the number of pregnancies and the number of offspring that survived until weaning. With administration of clonazepam to pregnant rabbits during the period of organogenesis at doses ranging from 0.2 to 10.0 mg kg−1 day−1, various malformations, including cleft palate, open eyelids, fused sternebrae, and defects of the limbs occurred at a low, non‐dose‐related rate. Pregnant rabbits given 5 mg kg−1 day−1 or higher doses exhibited reductions in maternal weight gain, while reductions in embryo‐fetal growth occurred at doses of 10 mg kg−1 day−1. However, no adverse effects were observed on the mothers, embryos, or fetuses when mice and rats were given doses up to 15 and 40 mg kg−1 day−1, respectively (Roche Laboratories 2001). Elimination of clonazepam from both plasma and the cerebral cortex becomes slower with age (Barnhill et al. 1990). Ranitidine and propantheline, which decrease stomach acidity, and fluoxetine, an SSRI, have little to no effect on the metabolism of clonazepam. Cytochrome P‐450 inducers, including phenytoin, carbamazepine, and phenobarbital, facilitate clonazepam metabolism, resulting in a 30% decrease in clonazepam levels in humans. Strong P‐450 3A inhibitors, such as oral antifungal agents, should be combined cautiously with clonazepam, because concurrent use may result in clonazepam overdose due to insufficient metabolism (Roche Laboratories 2001). Symptoms of overdose that are characteristic of CNS depressants may occur, including sedation, confusion, diminished reflexes, and coma. Gastric lavage should be initiated as soon as possible, followed by appropriate supportive treatment and monitoring of respiration, pulse, and blood pressure. Flumazenil, a benzodiazepine‐receptor antagonist, can be used to partially or completely reverse the effects, but should be avoided in patients that have been treated with clonazepam daily for an extended period of time because seizures may be induced. Initiate treatment at the lowest dose. If no undesirable side effects occur, titrate dose up to the desired effect. As with all benzodiazepines, clonazepam should be reduced gradually in patients that have been receiving it on a daily basis for several weeks. Clonazepam is not useful in the treatment of myoclonus caused by serotonin syndrome. In laboratory studies, clonazepam is substantially less toxic to cats than chlordiazepoxide, diazepam, or flurazepam (Table 7.3). Table 7.3 Dose at which muscle relaxation is achieved and lethal dose of some benzodiazepines when given orally to cats. Source: Randall and Kappell (1973). Note: The lethal dose for clonazepam is listed as >1000 mg kg−1 because this dose was not fatal, and higher doses were not given. The data are based on only two cats per benzodiazepine, and individual variation in metabolism would be expected to produce a wider range of doses than given in this table. However, the data show the relative differences between drugs in these effects. In a case report, Carter (2011) used clonazepam to treat noise phobias in a dog diagnosed with hyperactivity. This dog was treated initially with fluoxetine (which helped control the hyperactivity signs) but the patient still presented with noise phobias. The dog was less reactive to noises within a week of initiation of treatment. Clonazepam has been shown to have a taming effect on aggressive primates, with concurrent muscle weakness and hypnosis. Clorazepate is metabolized in the liver and excreted in the urine. In the acidity of the digestive tract, it is rapidly decarboxylated to form nordiazepam, also called desmethyldiazepam, which is the active metabolite (Troupin et al. 1979; Greenblatt et al. 1988). Plasma levels of nordiazepam will be proportionate to clorazepate dose. Nordiazepam is further metabolized by hydroxylation to conjugated oxazepam (3‐hydroxynordiazepam) and p‐hydroxynordiazepam (Abbott Laboratories 2004). Nordiazepam is also an active metabolite of diazepam. Clorazepate provides higher concentrations of nordiazepam over a longer period of time than does diazepam and has less sedative effect (Lane and Bunch 1990). After administration of a 50‐mg dose of clorazepate to humans, 62–67% of the radioactivity was excreted in the urine and 15–19% was excreted in the feces within 10 days (Abbott Laboratories 2004). As with other benzodiazepines, dogs metabolize clorazepate more rapidly than do humans. After administrations of oral clorazepate, humans have been reported to have a half‐life elimination of nordiazepam of 40.8 ± 10.0 hours (Wilensky et al. 1978) or over 80 hours (Boxenbaum 1980). In contrast, the half‐life of nordiazepam in dogs is about nine hours (Brown and Forrester 1991). In humans, Tranxene SD (sustained delivery) has longer efficacy than does the regular‐release product, Tranxene. In dogs, there is no difference in either time of peak plasma concentration or serum concentrations two hours after administration. However, 12 hours after administration of a single 2.5–3.8 mg kg−1‐dose serum concentration of regular release was 24 ± 77.9 ng ml−1 of nordiazepam, while serum concentration of nordiazepam with sustained delivery was 215 ± 66.1 ng ml−1 (Brown and Forrester 1991). There was no gender effect on disposition of the drug, although this study only involved four males and three females and so cannot be considered conclusive on this issue. Peak nordiazepam concentrations were 372–1140 ng ml−1 with the regular release. Peak nordiazepam concentrations were 450–1150 ng ml−1 with sustained delivery. Overall, the bioavailabilities of the two products were not different. In healthy adult dogs given a single dose of clorazepate orally at a dose of 2 mg kg−1 maximum nordiazepam concentrations at 59–180 minutes after administration range from 446 to 1542 ng ml−1. After multiple such doses given q12h, maximum nordiazepam concentration is reached at 153 ± 58 minutes and ranges from 927 to 1460 ng ml−1. The mean elimination half‐life after a single dose is 284 minutes, while the mean elimination half‐life after multiple doses is 355 minutes. After multiple doses of clorazepate, there are significant decreases in serum chemical values of albumin, total protein, and calcium, while there are significantly increased concentrations of urea nitrogen and glucose. There are also significant increases in total white blood cell count, segmented neutrophils, lymphocytes, and eosinophils. Urine pH decreases significantly. Also, serum alkaline phosphatase activity increases while alanine transaminase (ALT) values decrease. Despite these changes, all values remain within normal reference ranges after 21 days on 2 mg kg−1 b.i.d. (Forrester et al. 1990). Concurrent administration of clorazepate and phenobarbital in dogs results in significantly lower concentrations of nordiazepam, necessitating higher doses in dogs that are on phenobarbital because of epilepsy (Forrester et al. 1993). Clorazepate is used for management of anxiety disorders and short‐term relief of anxiety. Clorazepate is contraindicated in patients with a history of adverse reactions to clorazepate and in patients with acute narrow‐angle glaucoma. Since clorazepate has depressant effects on the CNS, avoid concurrent use with other CNS depressants. As with all benzodiazepines, sedation, ataxia, muscle relaxation, increased appetite, paradoxical excitation, increased friendliness, anxiety, and a variety of other side effects may occur. Transient sedation and ataxia were observed in one of eight healthy adult dogs given a single dose of 2 mg kg−1 of clorazepate (Forrester et al. 1990). Potential mutagenic effects of clorazepate have not been studied sufficiently to come to any conclusions. However, other minor tranquilizers, for example, diazepam, have been associated with an increased risk of fetal abnormalities if given during the first trimester of pregnancy. Nordiazepam is excreted in milk. Therefore, use of clorazepate in pregnant and nursing females should be avoided.
Benzodiazepines
Action
Overview of Indications
Contraindications, Side Effects, and Adverse Events
Overdose
Clinical Guidelines
Medication
Dogs
Cats
Alprazolam (Xanax)
0.02–0.1 mg kg−1 q4h
0.0125–0.25 mg kg−1 q8h
Chlordiazepoxide (Librium)
2.0–6.5 mg kg−1 q8h
0.2–1.0 mg kg−1 q12h
Clonazepam (Klonopin)
0.1–0.5 mg kg−1 q8–12h
0.015–0.2 mg kg−1 q8h
Clorazepate dipotassium (Tranxene)
0.5–2.0 mg kg−1 q4h
0.5–2.0 mg kg−1 q12h
Diazepam (Valium)
0.5–2.0 mg kg−1 q4h
0.1–1.0 mg kg−1 q4h
Flurazepam (Dalmane)
0.1–0.5 mg kg−1 q12h
0.1–0.4 mg kg−1 q12h
Lorazepam (Ativan)
0.02–0.5 mg kg−1 q8–12h
0.03–0.08 mg kg−1 q12h
Oxazepam (Serax)
0.04–0.5 mg kg−1 q6h
0.2–1.0 mg kg−1 q12–24h
Specific Medications
I. Alprazolam
Clinical Pharmacology
Uses in Humans
Contraindications
Side Effects
Overdose
Doses in Nonhuman Animals
Discontinuation
Other Information
Effects Documented in Nonhuman Animals
Cats
Dogs
II. Chlordiazepoxide HC1
Clinical Pharmacology
Uses in Humans
Contraindications
Side Effects
Overdose
Doses in Nonhuman Animals
Discontinuation
Other Information
Effects Documented in Nonhuman Animals
Cats
Dogs
Monkeys
Zoo Animals
III. Clonazepam
Clinical Pharmacology
Uses in Humans
Contraindications
Side Effects
Drug Interactions
Overdose
Doses in Nonhuman Animals
Discontinuation
Other Information
Effects Documented in Nonhuman Animals
Cats
Benzodiazepine
Muscle relaxation mg kg−1 PO
Lethal dose mg kg−1 PO
Chlordiazepoxide hydrochloride
2
200
Clonazepam
0.05
>1000
Diazepam
0.2
500
Flurazepam
2
400
Dogs
Other
IV. Clorazepate Dipotassium
Clinical Pharmacology
Uses in Humans
Contraindications
Side Effects
Dependence
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