Gabapentin was evaluated as an anxiolytic for spay/neuter surgery in 53 community cats in a trap-neuter-return (TNR) program (20). Using a double-blinded, placebo-controlled design, cats were given a single dose of placebo, low dose gaba-pentin (50 mg/cat), or high dose gabapentin (100 mg/cat) in a 1-mL sugar solution. A blinded observer scored each cat for fear, sedation, respiratory rate, and facial injuries at the time of administration, 1, 2, 3, and 12 h after administration. Regardless of dose, gabapentin reduced fear compared to placebo. Cats in this study weighed 1.4 to 5.4 kg (mean: 3.4 kg in 50 mg/cat group; 3.0 kg in 100 mg/cat group), resulting in dosages of 9.2 to 24.4 mg/kg BW (mean: 16.3 mg/kg BW) and 23.1 to 47.6 mg/kg BW (mean: 35.3 mg/kg BW), respectively. The cats in the placebo group overlapped with the excitement range on the CSS and mg/kg BW given overlapped for the 2 dosages, blurring evaluation of CSS by group. Feral cats are considered fractious which may affect CSS scores in ways not relevant for companion cats.
In a randomized, single-blinded, crossover study of 16 companion cats, Hudec and Griffin (21) administered either gaba-pentin or no treatment, then the reverse, in a 2-visit study to determine any effect of gabapentin on intradermal testing, cortisol, and glucose. Gabapentin was administered in capsules using a pre-determined mg/kg BW range, with an increase of 25 mg of gabapentin for up to each additional kilogram of weight beyond 2 kg. The maximal dosage range was 25 to 35.7 mg/kg BW. There was no effect of gabapentin on cortisol or glucose, but gabapentin correlated with lower stress assessments, although sedation could not be ruled out.
Sileo Dose In Cats
In a non-randomized, block design, single dosages of 10 and 20 mg/kg BW of gabapentin were given to 6 healthy grey-hound dogs, 1.5 to 3 y old, to determine pharmacokinetic parameters (22). Mean dosages administered were 10.2 mg/kg BW (range: 9.1 to 12.0 mg/kg BW) and 20.5 mg/kg BW (range: 18.2 to 24 mg/kg BW), respectively. Cmax occurred at 1.3 and 1.5 h, and the terminal half-lives were 3.3 and 3.4 h, respectively for each dose group. These findings were similar to the 2.9 h Cmax reported for intravenous dosing in dogs at 25 mg/kg BW per day for 14 d and 100 mg/kg BW per day for 28 d (n = 2 beagle dogs) (23). The t1/2 of oral gabapentin was 3 to 4 h in dogs, 2 to 3 h in rats and 5 to 6 h in humans (24). Rapid absorption and elimination suggest the need for frequent dosing to maintain targeted plasma concentrations (24). Dogs, unlike cats and humans, metabolize about 34% of gabapentin to N-methyl-gabapentin (23,24).
Rhee et al (25) compared a gabapentin 600 mg single dose sustained release formulation with a single dose immediate release formulation in 4 fasted beagle dogs, 10 to 12 kg (50 to 60 mg/kg BW). There were concerns with dissolution and absorption of the sustained release tablet, but the plasma concentration versus time curves were similar for both formulations with fully overlapping error bars. For the immediate release formulation, used in all studies reported here, time to reach Cmax (Tmax) was 2.0 0.0 h and t1/2 was 3.2 0.2 h.
Although there are multiple pharmacokinetic studies in dogs and gabapentin is widely used by specialists for fear and anxiety at the equivalent dose recommended for pain (20 mg/kg BW) or greater (26), there are no published clinical studies on the use of gabapentin to decrease situational anxiety in dogs. Such studies are needed. Given the studies in cats and anecdotal specialist usage (26), the anxiolytic dose of gabapentin may be higher than the analgesic dose, as in humans (14,15), but this clinical impression requires testing.
In a randomized study (n = 6 cats), evaluation was as a sedative for transport and examination (32). Each cat served as its own control and was given a single dose of each of 4 treatments over 4 wk: placebo and 1 dose each of 50, 75, and 100 mg trazodone (10.6 to 16.7 mg/kg BW, 16.0 to 25 mg/kg BW, and 21.3 to 33.3 mg/kg BW, respectively). Sedation was measured by accelerometry, the CSS, and behavioral measures. Peak sedation occurred 2.5 h after the 100 mg dose, although the range across this small group of cats was wide, extending to 3 h. CSS did not differ at any time point between placebo and treatment groups, suggesting that the clinical effect was one of true sedation, not anxiolysis. The largest proportional sedative effect occurred after the 50 mg dose, suggesting that it may be sufficient for transport and clinical evaluation.
Stevens et al (32) compared a 50 mg trazodone dose (7.7 to 15.2 mg/kg BW) to a placebo in a single-blinded, randomized study with 10 client-owned cats with a history of distress related to transport and/or examination. Cats were medicated 90 min before travel and examination. Clients used the CSS and a tool to score tractability before, during, and after transport and examination. Veterinarians evaluated the cats before, during, and after examination. Cats given trazodone exhibited less stress before transport (P = 0.02), in the waiting room (P = 0.02), during veterinary examination (P = 0.04), and after (P = 0.008) the examination. This study did not differentiate between sedation and anxiety relief, nor did it evaluate post-examination recovery. The difference between anxiety relief and sedation may not matter to clients or patients since the cat does not experience distress, but clients should know about it and that recovery period from sedation is variable.
Trazodone has been evaluated for use in management of anxiety in hospitalized dogs (34). Hospitalized dogs displaying any behavioral signs of stress or distress (n = 59) were administered trazodone at 4 mg/kg BW, PO, q12h, with the dose or frequency increased to 10 to 12 mg/kg BW or to every 8 h when needed for desired calming and anxiolytic effects (not to exceed 300 mg/dose or 600 mg/24 h). In this observational study, dogs were matched with an untreated nearby dog (n = 58) to control for environmental effects. Dogs were evaluated at 45- and 90-minute post-treatment for 22 stress-related behaviors. Lip licking, panting, and whining decreased significantly in the dogs receiving trazodone. Sedation and other functional and physiological parameters were not measured. The results suggest that trazodone be given 90 min before the examination.
Wide dosage ranges have been reported for trazodone in both cats and dogs. No source stated a recommended dose, although Gilbert-Gregory et al (34) recommended a maximum of 300 mg/dose or 600 mg/24 h in dogs.
In a block randomization study comparing injectable versus oral buprenorphine (20 μg/kg BW) combined with dexmedetomidine (20 μg/kg BW) to facilitate catheter insertion in cats, OTM injectable dexmedetomidine allowed for easier catheter placement than did injectable dexmedetomidine, and produced less sedation (38). Benefits of OTM administration were decreased aversion for cats to the administration route and decreased risk of accidental needle sticks to humans (38). Differences in sedation associated with route may be due to decreased bioavailability associated with salivation, vomiting, and swallowing (which inactivates the compound). Less compound crossed the mucous membranes into the bloodstream than occurred with injection. When salivation or vomiting was minimal, oral and injectable administration had similar sedative effects (38).
Oral transmucosal dexmedetomidine gel (Sileo; Zoetis) was tested for alleviation of fear of fireworks noise in a randomized, double-blinded, placebo-controlled clinical study (41). With sub-sedative doses of 125 μg/m2 (4.65 μg/kg BW in a 20 kg dog), dogs in the treatment group were statistically significantly less distressed and fearful than dogs in the placebo group, with an excellent or good effect reported for 72% of the dogs treated with dexmedetomidine than 37% of those treated with a placebo. Dogs in the dexmedetomidine treatment groups expressed significantly fewer signs of fear and anxiety (panting, trembling, pacing, elimination) while listening to fireworks. Based on a functional alertness assessment scale, > 85% of the dogs in the treatment groups remained fully functional throughout the event. The most severe effect reported was emesis (41).
Oral transmucsoal dexmedetomidine gel is dosed at 125 μg/m2 body surface area (each mL = 0.1 mg dexmedetomidine; 3 mL per syringe; 1 dispensing dot = 0.25 mL/25 μg) (43). For those lacking access to the licensed product, 25 to 40 μg/kg BW of the injectable dexmedetomidine has been given OTM (39). The anti-anxiety dose is lower than the sedative dose, but not established for OTM injectable dexmedetomidine.
The starting range is 0.02 to 0.04 mg/kg BW (44), but dosages as high as 0.1 mg/kg BW have been reported (12,47). In cats, the published dose range is 0.0125 to 0.025 mg/kg BW/0.125 to 1 mg/cat (48). There are no dose determination studies for alprazolam in cats and dogs.
The major adverse effect reported with use of benzodiazepines is sedation. Alprazolam is less sedative than diazepam and most adverse effects of benzodiazepines, including sedation and ataxia, are dose-dependent (12,49). Paradoxical excitement has been reported in cats and dogs, as has disinhibition of previously inhibited behavior (e.g., aggression) (12,46,49). Benzodiazepines are well-known for highly individually variable responses so recommendations are to start at a low dose and have clients give the first dose or two when they are at home to monitor their pet for any adverse reactions. Extremely rare, long-lasting adverse reactions or those posing a risk to the patient can be reversed with IV flumazenil.
Of the 4 medications for which there was published information, 3 are not licensed for use in dogs or cats. Except for the licensed OTM dexmedetomidine, pharmacokinetic data are sparse and dose determination studies are lacking. This pattern is problematic. The existence and publication of these data would provide veterinarians with a greater comfort level in dispensing the medications discussed. 2ff7e9595c