In the last post, Dr. Hofmeister chemically restrained a vicious werewolf using an intramuscular combination of sedatives and anesthetic agents, thereby saving his camping party from certain doom.
But what if that vicious werewolf were actually just a terrified pup defending herself from menacing strangers in a new and frightening environment? And what if we could lessen the fear and prevent some of the aggressive behaviors by having the werewolf’s owner administer oral medications to take the edge off?
There are many options when it comes to oral sedatives to calm patients for transport, cage confinement, and prior to visits to the veterinary clinic. The following are some of the most popular choices.
Gabapentin
Gabapentin, and its close relative pregabalin, are thought to exert their effects – and side effects – by interacting with voltage-gated calcium channels in the dorsal root ganglion, spinal cord, and supraspinal regions, decreasing synaptic transmission. Traditionally used as a second-line anticonvulsant, gabapentin is also prescribed off-label for humans in the management of neuropathic pain, certain mood and anxiety disorders, and restless leg syndrome. Recently, the veterinary medical community has moved towards using gabapentin as an adjunct analgesic agent and has also been employing it as a primary analgesic agent, though the latter is likely to be a misguided - if well-intentioned - use of the drug.
The primary side effect of short term administration of gabapentin is somnolence – which is why it comes in handy for us as an oral pre-visit sedative! Gabapentin works particularly well in cats to decrease reactivity to transport and veterinary visits. (1, 2)
The typical starting dose is about 20 mg/kg but this can be increased dramatically. I give my own 9 year old cat, Socks, 40 mg/kg of gabapentin the night before and the morning of when I need to bring him for his biannual echocardiograms. This makes it much more enjoyable for everyone!
Gabapentin is not currently controlled at the federal level in the US but several states, including Kentucky, Virginia, and Michigan have done so. Also, beware that the liquid version of the brand name, Neurontin, is formulated with xylitol. Xylitol is documented to cause liver damage and hypoglycemia in dogs but has not been reported to be toxic for cats.
Trazodone
Trazodone is an atypical antidepressant that antagonizes a subtype of serotonin receptors and also inhibits serotonin reuptake. It is commonly prescribed in humans for a variety of psychiatric and medical diagnoses, including depression and insomnia. It has been used as an adjunct for canine anxiety disorders (3) as well as to facilitate post-surgical cage rest (4) and has been shown to reduce outward signs of stress and anxiety in hospitalized dogs. (5) In addition, trazodone has been documented to reduce signs of stress associated with transport and veterinary examination in cats. (6)
As with gabapentin, it is the side effect of causing drowsiness and reducing behavioral signs of anxiety that makes trazodone useful for us. For ultra-short-term use (administered once or twice prior to transport), 5 - 10 mg/kg is a good dose to try. For longer use in the patient who needs to tolerate cage confinement, start with around 2 - 4 mg/kg q8h and then titrate upward.
In humans, trazodone can precipitate or unmask long QT syndrome, potentially leading to polymorphic ventricular tachycardia. This syndrome is basically not a thing in dogs and cats but I still pay pretty close attention to the ECG when using trazodone prior to anesthesia because it is possible that unexpected effects might occur once other sedatives and inhalant anesthetics are thrown into the mix.
In addition, trazodone is what I would refer to as an ODD – an Old, Dirty Drug. It is not like the new fancy (expensive) highly receptor targeted drugs; it has effects at lots of receptors, including alpha-1 and histamine receptors as well as calcium channels. Because of this receptor activity profile, hypotension may occur, especially when administered at high doses.
Finally, the serotonergic action of trazodone makes it possible that combining it with other serotonergically active drugs – including various antidepressants, tramadol, and even some opioids – could precipitate serotonin syndrome.
Benzodiazepines
Benzodiazepines modulate neurotransmission by promoting activity of GABA, the major inhibitory neurotransmitter. When administered orally to dogs and cats, benzodizepines can provide mild sedation and anxiolysis. This group of drugs causes minimal cardiorespiratory effects at typical doses; however, there are several real drawbacks to the use of oral benzodiazepines:
1) Disinhibition is possible; this may actually worsen aggressive behavior
2) Paradoxical excitement can occur (though this is much more common with injectable administration)
3) Oral diazepam has led to hepatic failure in cats
4) These are federally controlled drugs
Although oral benzodiazepines certainly have a role in management of behavioral issues, we luckily have other choices available for short-term diagnostic- and treatment-related anxiety and aggression.
Acepromazine
Another ODD! Acepromazine exerts is sedative effects through antagonism of dopamine receptors in the central nervous system, but it also antagonizes histaminic, muscarinic, and alpha-1 receptors. Significant cardiovascular side effects can occur, including hypotension and tachycardia.
Although oral administration of acepromazine has long been popular to reduce the behavioral signs of anxiety and aggression in animals, there is some evidence that the drug does little to calm the patient internally. In fact, human case reports from the middle of the last century with the related drug chlorpromazine indicate that the loss of the ability to assume defensive behaviors actually increased internal struggle: “That is to say, the patient had been slowed, felt tired, was calmed, and had his activity cut, and it was precisely this physiological effect that was psychologically threatening to the patient”. (7)
Acepromazine has a place in oral sedation protocols but is best used in combination with other drugs that more predictably provide anxiolysis (see the Chill Protocol below).
Phenobarbital
An oral barbiturate, phenobarbital facilitates GABA activity in the CNS, similarly to benzodiazepines, but can also directly activate the GABA receptor. This drug is typically prescribed for its anticonvulsant properties but its major side effect – sedation – can be useful to us prior to stressful events. The generally recommended dose for short-term sedative effects is 10 mg/kg. Phenobarbital should be used with caution or not at all in patients with pre-existing hepatic dysfunction. It is, of course, a controlled drug.
Oral transmucosal dexmedetomidine
Oral transmucosal gel versions of the alpha-2 agonists detomidine (marketed for horses) and dexmedetomidine (Sileo – marketed for noise phobias in dogs) are available. Alpha-2 agonists reduce norepinephrine concentrations in parts of the brain responsible for arousal and can be used to facilitate examination and minor procedures. The dexmedetomidine gel can be administerd at 30 – 50 mcg/kg via the oral mucosa.
However, alpha-2 agonists have some real drawbacks that must be kept in mind:
1) Profound increases in systemic vascular resistance occur, resulting in decreased heart rate and cardiac output
2) If the gel contacts a human mucous membrane, toxicity could occur. Gloves and eye protection are best
3) Patients may be rousable and an alpha-2 agonist alone should not be relied on in dangerous animals
Combinations
For some patients, combinations of the above-mentioned drugs may be necessary to achieve the desired effect. In these situations, it may just take a bit of trial and error to find the right combination at the right doses. A common combo includes trazodone ~ 5 mg/kg and gabapentin ~ 20 mg/kg given 2 to 3 hours prior to travel.
Another option is The Chill Protocol developed by Dr. Alicia Karas at Tufts University:
The evening before:
Gabapentin 20 – 25 mg/kg PO
1-2 hours prior:
Gabapentin 20 – 25 mg/kg AND
Melatonin (small dogs 0.5 -1 mg; medium dogs 1 - 3 mg, large dogs 5 mg) PO
30 minutes prior:
Injectable acepromazine 0.025 – 0.05 mg/kg oral transmucosal
Timing is very important with this protocol and all the drugs must be given as directed. The folks at Tufts use a client handout with very specific instructions about when to give the medications.
Whatever oral sedative/anxiolytic you chose, you may need to follow with injectable agents in order to do more invasive/scary procedures. If the patient is quite sedated from the oral medications, then you will want to select drug doses on the lower end of the ranges. As always, safety in anesthesia is about good monitoring and supportive care! Make sure you keep an eye on the patient continuously once injectable drugs are administered, attach objective monitors such as a pulse oximeter and BP cuff, supplement oxygen, and be prepared to take care of the patient’s physiology for them if they can no longer do so - that is, be ready to intubate, ventilate, and support blood pressure and perfusion.
Finally, remember that oral sedatives are only part of the answer. Listen to what the patient is telling you with their body language and respect it. Try to integrate low stress handling techniques into your practice culture. And don’t be afraid to use injectable agents to prevent struggling and increased fear responses.
References:
1 Pankratz KE, Ferris KK, Griffith EH, Sherman BL. Use of single-dose oral gabapentin to attenuate fear responses in cage-trap confined community cats: a double-blind, placebo-controlled field trial. J Feline Med Surg. 2018 Jun;20(6):535-543.
2 van Haaften KA, Forsythe LRE, Stelow EA, Bain MJ. Effects of a single preappointment dose of gabapentin on signs of stress in cats during transportation and veterinary examination. J Am Vet Med Assoc. 2017 Nov 15;251(10):1175-1181.
3 Gruen ME, Sherman BL. Use of trazodone as an adjunctive agent in the treatment of canine anxiety disorders: 56 cases (1995-2007). J Am Vet Med Assoc. 2008 Dec 15;233(12):1902-7.
4. Gruen ME, Roe SC, Griffith E, Hamilton A, Sherman BL. Use of trazodone to facilitate postsurgical confinement in dogs. J Am Vet Med Assoc. 2014 Aug 1;245(3):296-301
5 Gilbert-Gregory SE, Stull JW, Rice MR, Herron ME. Effects of trazodone on behavioral signs of stress in hospitalized dogs. J Am Vet Med Assoc. 2016 Dec 1;249(11):1281-1291.
6. Stevens BJ, Frantz EM, Orlando JM, Griffith E, Harden LB, Gruen ME, Sherman BL. Efficacy of a single dose of trazodone hydrochloride given to cats prior to veterinary visits to reduce signs of transport- and examination-related anxiety. J Am Vet Med Assoc. 2016 Jul 15;249(2):202-7.
7. Sarwer-Foner GJ & Ogle W. Psychosis and enhanced anxiety produced by reserpine and chlorpromazine. Can Med Assoc J. 1956 Apr 1;74(7):526-32.