Oral transmucosal administration of dexmedetomidine for sedation in 4 dogs

Abstract

Injectable dexmedetomidine (DM) is widely used for sedation, restraint, anxiolysis, and analgesia in veterinary medicine. Oral transmucosal dexmedetomidine (OTM DM) has been evaluated in horses, cats, and humans, but not in dogs. In this case series, OTM DM (mean dose of 32.6 μg/kg body weight) was given in the buccal pouch to 4 aggressive dogs in a hospital setting. Two of the dogs were subsequently euthanized, and in the other 2, sedation was reversed with atipamezole. Satisfactory sedation was achieved in all cases.

Alpha-2 adrenergic agonists are widely used in veterinary medicine to induce sedation, anxiolysis, and analgesia. Common alpha-2 adrenergic agonists used in veterinary medicine include dexmedetomidine (DM), medetomidine, xylazine, and detomidine. Dexmedetomidine is commonly given by IM and IV routes in small animals. Many studies have observed safe and effective oral transmucosal administration (OTM) of DM in cats, horses, and humans (1–7).

Alpha-2 adrenergic agonists activate alpha-2 receptors in the central nervous system resulting in attenuation of norepinephrine to decrease arousal and inhibit afferent pain pathways (8,9). Central and peripheral alpha receptor activation produces cardiovascular, gastrointestinal, and other effects (9,10). In addition to providing potent sedative and analgesic effects, alpha-2 adrenergic agonists can also be reversed with alpha-2 adrenergic antagonists, such as atipamezole, adding to its value for short procedures, restraint, and patients who display unwanted or harmful side effects (8,9).

As many as 78.5% of dogs have been reported to exhibit fear during visits to the veterinary clinic (10). Learning can perpetuate fear during veterinary visits and can lead to future increases in fear, heightened behavioral and physiologic responses in patients, and can result in owner stress, patient panic, and aggressive response (11). Fear and, in particular, aggression can make administration of chemical restraint by IM or IV injection by veterinary staff difficult or dangerous. Orally administered medication prior to a veterinary visit may not be possible due to owner noncompliance and inconsistency of desired effect.

There is no standardized sedation score in veterinary medicine, but several sedation scores exist in human medicine, such as the University of Michigan Sedation Scale (UMSS) visual analogue scale (VAS), and the Observer’s Assessment of Alertness/Sedation Scale (OAAS) (12). One scale has been used in veterinary medicine along with similar modified versions (13–15). This scale assessed the sedative effects by evaluation of spontaneous posture (scores 0–4), palpebral reflex (0–3), position of the eye (0–2), relaxation of the tongue and mandible (0–4), response to sounds (hand clap) (0–2), resistance to physical restraint in lateral recumbency (0–3), and general appearance (0–4) (Table 1). A score of 0 represents no response and a score of 3 or 4 represents a profound response. A summation of these parameters gave a total sedation score of 0 to 22.

Table 1.

Description of sedation rating system. The sedation score was the sum of all subscores

Assessment	Subscore and definition
Posture	0: Standing position, normal proprioception (animal walks without ataxia) 1: Animal remains in sternal or lateral position but is able to stand when stimulated verbally 2: Remains in sternal recumbence 3: Lateral recumbency, eventually moves or lifts head 4: Lateral recumbency, if not verbally stimulated does not move or lift its head
Eyelid reflex	0: Strong lateral and medial eyelid reflexes 1: Lateral and medial eyelid reflexes present but reduced 2: Lateral eyelid reflex absent and medial eyelid reflex present 3: Lateral and medial eyelid reflexes absent
Eye globe position	0: Eye centrally positioned 1: Partial rotation of the eye globe 2: Full rotation of the eye globe
Relaxation of the tongue and mandible	0: Normal tone of the mandible and tongue 1: Reduced tone of the mandible and tongue, allowing opening of the mandible with little difficulty; tongue can be exposed with some difficulty and is readily retracted after release 2: Reduced tone of the mandible, tongue can be easily exposed but is readily retracted after being released 3: Mouth can be easily opened with jaw tone markedly reduced, tongue can be easily exposed, but animal retracts the tongue a few seconds after being released 4: Mandible and tongue fully relaxed, tongue can be exposed and it is not retracted after being released
Response to sound (clapping)	0: Alert attitude, readily reacts (looks, lifts head) to the stimulus 1: Reduced reaction (discrete movement, lifting of the head); however, the animal appears sedated 2: No reaction or movement
Resistance to physical restraint in lateral recumbency	0: Animal resists; readily returns to standing position or sternal recumbency after being released 1: Offers little resistance, but readily returns to standing or sternal recumbency after being released 2: Does not offer resistance, but eventually moves or lifts its head and returns to sternal recumbency 3: Remains in lateral recumbency, does not offer resistance
General appearance	0: Alert, normal consciousness 1: Animal lightly sedated, promptly reacts or moves in response to environmental stimulation 2: Animal moderately sedated, eventually reacts to environmental stimulation 3: Animal appears to be moderately to deeply sedated, reduced reaction to environmental stimulation 4: Animal appears to be deeply sedated, does not react to environmental stimulation

To the authors’ knowledge there are no published reports on the use or efficacy of DM hydrochloride injectable liquid administered by the oral transmucosal (OTM) route to aid in examination and handling of apparently healthy, aggressive dogs. This report illustrates the safe and successful use of DM hydrochloride injectable given OTM to healthy dogs.

Case descriptions

Case 1

A 2-year-old, 21.8 kg, neutered male, mixed breed dog was presented to the behavior service at VCA Berwyn Animal Hospital (BAH) for evaluation of aggression toward his owners. Medical history included deafness and anisocoria since puppyhood and otitis externa auris sinistra. The owners were unable to treat the otitis due to aggression while attempting to handle the dog. Over the previous 3 mo the dog bit his owners 3 times — including one episode the morning of presentation. Triggers for his aggression, manifested by growling and repeated lunging and biting, included the presence of food nearby, his owners reaching for a leash attached to his flat collar, someone standing up while in the same room with him, touching his feet or ears and applying topical flea and tick preventive or ear medication. The patient was diagnosed by a board-certified veterinary behaviorist with generalized anxiety, severe possessive aggression, fear aggression with handling and conflict-related aggression directed to his owners. Due to the presence of congenital neurologic abnormalities, a neurologic etiology for the aggressive behavior could not be ruled out. Referral to neurology service was offered but declined. Behavioral management and behavior modifying medication were offered but not pursued by the owners due to the risk of possible increased aggression and inability to manage the pet safely at home. Humane euthanasia with sample submission for rabies was elected due to the high risk of further aggressive episodes during a quarantine period.

Prior to administration of any medication, the sedation score was 0 (Table 2). Dexmedetomidine (Dexdomitor HCl; Orion Corporation; Zoetis, Kalamazoo, Michigan, USA) and methadone (Methadone HCl; Mylan, Rockford, Illinois, USA) were administered IM at 13.76 μg/kg body weight (BW) and 0.1 mg/kg BW, respectively. A total of 27.5 μg/kg BW of DM and 0.2 mg/kg BW of methadone were prepared for the patient but the entire volume could not be administered due to patient aggression manifested by spinning, lunging, and trying to bite the syringe and staff despite restraint with 2 leashes. Ten minutes after the first IM injection, the sedation score was 0. DM, 34.4 μg/kg BW, was sprayed into the mouth using a 3 mL syringe with a 22-gauge hypodermic needle using forceful pressure on the syringe plunger from a distance of 0.6 m. A small volume of DM was administered into the right conjunctival sac when the patient lunged forward. One minute later the sedation score was 8 to 9. Since we were unsure if this entire volume was absorbed, another 13.76 μg/kg BW of DM was administered IM (total dosage 34.4 μg/kg BW, OTM and 27.5 μg/kg BW, IM) to ensure effective sedation and safe handling with a resulting sedation score of 16 (Table 2) and a basket muzzle was safely placed. For humane euthanasia, a butterfly catheter was used to administer pentobarbital sodium (Euthasol; Virbac, Fort Worth, Texas, USA), 304.2 mg/kg BW, into the lateral saphenous vein. Rabies test was negative as reported by the Illinois Department of Public Health.

Table 2.

Total sedation score by case

	Case 1				Case 2		Case 3			Case 4
Time (min)	0	10	11	13	0	15	0	10	34	0	4	10	18
Posture	0	0	3	4	0	0	2	3	3	0	0	0	2
Eyelid reflex	NP	NP	NP	NP	NP	NP	0	1	2	NP	NP	NP	2
Eye globe position	0	0	NP	2	0	1	0	1	1	0	0	0	1
Relaxation of tongue and mandible	NP	NP	NP	3	0	1	0	0	1	0	0	0	1
Response to sound (clapping)	NP	NP	NP	NP	0	1	0	0	1	0	0	0	1
Resistance to restraint in lateral recumbency	NP	NP	2–3	3	0	1	0	0	3	0	0	0	2
General appearance	0	0	3	4	0	1	0	1	1–2	0	0	0	3
Total sedation score	0	0	8–9	16	0	5	2	6	12–13	0	0	0	12

NP — not performed.

Case 2

A 5-year-old, 34.1 kg, neutered male, pit bull terrier was presented to the BAH for 10-day rabies observation quarantine after biting someone earlier in the day. Prior to presentation the patient was seen at a referring hospital where rabies, Bordetella bronchiseptica, and distemper/parvovirus/adenovirus/ parainfluenza vaccines were administered (unknown manufacturers). Details of the bite incident were not obtained. There was no pertinent prior medical history. On initial examination, the patient was muzzled by the owners due to lunging at veterinary staff in the examination room. His pupils were mydriatic during examination. No other abnormalities were observed on examination or during the 10-day quarantine. The rabies observation release examination was performed on day 10.

Prior to examination the patient’s sedation score was 0 (Table 2). Due to the presence of aggression and his history of biting, the dog was observed for neurologic deficits during ambulation at a distance without physical restraint. Safe application of a muzzle was not possible without sedation due to growling and lunging. Dexmedetomidine, 16.1 μg/kg BW, was sprayed into the mouth using a 3 mL syringe with a 22-gauge hypodermic needle using forceful pressure on the syringe plunger from a distance of 0.6 m. Total sedation score 15 min after DM administration was 5 (Table 2) with the patient still in a standing posture. A basket muzzle was safely placed as the patient was no longer lunging or growling. Examination with sedation revealed no abnormalities. Heart rate during the examination was 100 to 120 beats/min and the respiratory rate was 18 breaths/min. No other monitoring was performed. Reversal of the DM was achieved by IM injection of 0.16 mg/kg BW atipamezole hydrochloride (Antisedan, Orion; Pfizer) into the left epaxial muscles. No adverse side effects were observed during sedation or after reversal.

Case 3

An 8.5-year-old, 38.7 kg, intact male German shepherd dog was presented to BAH for euthanasia due to quality of life concerns, suspected to occur from rapid progression of degenerative myelopathy. He was a high performance police dog that had been retired 7 d earlier due to progressive T3-L3 myelopathy. Prior medical history included a hemilaminectomy, osteoarthritis, allergic dermatitis, otitis externa, and a root canal 4 y ago. On the day of euthanasia and at previous visits the patient displayed signs of extreme anxiety with panting, pacing, and hypervigilance. Prior to euthanasia, DM was administered OTM to reduce anxiety and resultant risk for aggression during intravenous catheter placement.

A total dosage of 40 μg/kg BW of DM solution was administered directly into the left cheek pouch with a 6-mL dosing syringe. Prior to administration of DM the patient had a sedation score of 2 (Table 2). At that time he was sternally recumbent due to non-ambulatory paraparesis, but had normal mentation and was very attentive to his handler, consistent with his level of work and training. Within 3 min, the mucous membrane and tongue color changed from pink to pale pink. After 8 min, the mucous membranes were white. He began to drool and 10 min after administration he had a sedation score of 6. Thirty-four minutes after DM administration the sedation score was 12 to 13 (Table 2) with the patient consistently in lateral recumbency. A catheter was placed intravenously with minimal restraint and the patient was euthanized with 120 mg/kg BW of pentobarbital sodium.

Case 4

A 2-year-old, 33.2 kg, male intact pit bull terrier was presented to BAH for determination of complete blood cell count, biochemistry profile, total thyroxine, vector-borne disease screening, and urinalysis. Treatment with fluoxetine was initiated 1 mo earlier by a board-certified veterinary behaviorist after diagnosis of severe generalized anxiety, global fear, and fear/territorial aggression. He had no pertinent prior medical history. The patient was growling, barking, and lunging at veterinary staff. A Gentle Leader (Petsafe, Knoxville, Tennessee, USA) head collar and basket muzzle were placed by the owner for restraint and handling, but the dog still could not be safely approached.

Prior to administration, the patient’s sedation score was 0 (Table 2). An initial dosage of 15 μg/kg BW was administered via a 3-mL dosing syringe by the owner into the right cheek pouch through the basket muzzle. Dexmedetomidine was administered by the owner due to lack of patient compliance with handling and risk of aggression to veterinary staff. Four minutes later, the patient began to reverse sneeze. The patient was slightly less reactive to veterinary staff and noises outside of the examination room but continued to growl, bark, and lunge if approached. Sedation score was 0. Ten minutes after the first dose, an additional 25 μg/kg BW was administered into the right cheek pouch by the owner (total dosage 40 μg/kg BW, OTM). Within 1 min the patient’s eyes relaxed into a ventral position and the patient willingly moved into sternal recumbency. At 16 min, the patient had breakthrough barking to a noise outside of the room and after 18 min no further episodes occurred despite noises or veterinary staff walking past the examination room. The sedation score was 12. The owner tested the eyelid reflex and determined the level of relaxation of the tongue and mandible via direction from a veterinarian (AC). A physical examination was performed under DM sedation which showed a respiratory rate of 18 breaths/min, heart rate of 50 to 60 beats/min, and the remainder of the examination was normal. Blood was collected via a 22-gauge needle attached to a 3-mL syringe. Two minutes later, atipamezole, 0.04 mg/kg BW, was administered IM into the right epaxial muscles. Within 9 min, the patient was bright, alert, and responsive and eating small treats. The patient was walked out of the hospital. A follow-up phone call with the owner the next day confirmed that the patient showed no adverse effects at home. All laboratory parameters were within normal limits.

Discussion

This report describes the safe and effective use of dexmedetomidine hydrochloride injectable solution given oral-transmucosally to healthy and aggressive or severely anxious dogs for sedation for examination, drawing of blood, or IV catheter placement for humane euthanasia. Initial OTM dosages were extrapolated from previous studies such that a total of 40 μg/kg BW was not exceeded (1,7). The mean total OTM dosage used in the 4 cases in this report was 32.6 μg/kg BW, with a range of 16.1 to 40 μg/kg BW. Oral transmucosal administration of DM to the dogs in this study resulted in reliable sedation such that safe restraint was possible. Dexmedetomidine injectable dosage is 500 μg/m² IM or 375 μg/kg IV for sedation (16).

Dexmedetomidine is the active, dextrorotatory enantiomer of the racemic mixture medetomidine, an alpha-2 adrenergic agonist. Stimulation of presynaptic alpha-2 adrenoreceptors creates a decrease in norepinephrine release both centrally and peripherally leading to a decrease in both CNS sympathetic outflow and circulating catecholamines (9,17). Cardiovascular effects of alpha-2 adrenergic agonists include bradycardia with associated bradyarrhythmias (1st and 2nd degree atrioventricular heart block), reduction in cardiac output by up to 50%, increase in systemic vascular resistance, and hypertension or hypotension. Side effects include respiratory depression, hypothermia, muscle twitching, vomiting, cyanosis, muscle relaxation, inhibition of colonic motility, mydriasis or miosis, and decreased cerebral blood flow therefore decreasing intracranial pressure (18). These side effects have been reported with IM and IV administration of DM. Dexmedetomidine and other alpha-2 adrenergic agonists should be reserved for use in cardiovascularly stable, otherwise healthy animals due to their potential side effects. Dogs previously given detomidine gel OTM displayed bradycardia, transient second-degree atrioventricular block, respiratory depression, localized vasoconstriction as evidenced by pale oral mucous membranes, and enuresis (7). Cats administered DM OTM displayed vomiting, salivation, and resistance to administration (1,19,20). In this case series, the dog in Case 3 developed pytalism, pale to white mucous membranes and tongue color, most likely secondary to localized vasoconstriction from the DM OTM, which can also observed with injectable DM.

Hemodynamic and cardiovascular measurements were not obtained in this case series. However, there were no observed adverse events requiring medical intervention. Two of the 4 patients in this study were given DM prior to humane euthanasia and undesirable effects of DM would not have affected the outcome. Due to the potential for unwanted side effects, the authors in this report recommend that DM given OTM should only be used in cardiovascularly stable, healthy dogs with attentive monitoring.

Alpha-2 adrenergic-agonists administered OTM have proven safe and effective for sedation in humans, horses, and cats. Benefits in humans and animals given DM OTM are a non-invasive approach to administration and decreased physiologic response (2–4) and, in some cases, superior sedative and antinociceptive effects (2). Dexmedetomidine is tasteless, odorless, and painless and seems to be well-absorbed systemically through the oral mucosa with buccal bioavailability as high as 82% in adult humans (4,21). Sedation was significantly higher in humans given DM orally than in humans given a diazepam suppository (3). In another retrospective study in humans, adequate sedation was achieved for procedural and anesthetic premedication with bucally administered DM (22). In a study of 75 adults undergoing arthroscopic knee surgery, buccally administered DM for premedication provided equal levels of sedation and anxiolysis and more evident analgesia compared with IM administration (2). Sublingual administration of detomidine oromucosal gel produced safe sedation in horses with fewer and less pronounced adverse effects than IM administration (6). In cats, DM was well-absorbed through the oral mucosa and both OTM and IM administration produced similar overall sedative and antinociceptive effects (1). Detomidine hydrochloride gel was safely administered to 6 dogs resulting in measurable signs of sedation, anxiolysis, and ease of handling (7).

Sedation through OTM or the buccal route can be more variable than IV or IM administration due to swallowing of the orally delivered dose, loss of the drug outside of the mouth, expelled medication by coughing or spitting, or vomiting or ptyalism reducing or diluting the quantity of drug for absorption. Absorption through oral mucous membranes is affected by the pKa and lipophilicity of a drug, tissue perfusion, and uptake. Dexmedetomidine has a relatively low molecular weight that also facilitates absorption (1,21). When vomiting and salivation are minimal or absent, systemic bioavailability of dexmedetomidine given by the OTM route is reported to be similar to that of the IM route in cats (23).

The investigators chose the current sedation score because it was user friendly and assessed many indicators of an individual’s alertness or arousal. This scale was previously utilized to evaluate the sedative and cardiorespiratory effects of acepromazine and atropine given before DM in dogs and in other studies (13–15). Most of the parameters of this scale could be observed from a distance, making assessment of aggressive dogs feasible. For assessment parameters such as eyelid reflex and relaxation of the tongue and mandible, where hands-on evaluation is necessary, scoring was not performed in some cases due to concern for safety during evaluation. Relaxation of the tongue and mandible were assumed to be 0 without sedation and documented as such. Based on the small number of dogs in this case series, we were not able to determine a sedation score necessary for safe restraint and handling. Though the goal of sedation in the present study was for safe restraint, the sedation score necessary for safe handling was found to vary from dog to dog — dependent on the level of arousal and aggression displayed. However, there was clearly a change from the baseline pre-sedation score to the post OTM DM sedation score in all 4 dogs.

This report found that the mean time for sedation was 19.5 min (range: 11 to 34 min) such that basket muzzle placement or safe restraint could be performed. Time to sedation was not prohibitive for OTM administration of DM to dogs in the clinical setting. The dog that took the longest to exhibit signs of sedation was the police dog; this may have been secondary to high levels of endogenous catecholamines seen in stressed or agitated animals (9) or due to his heightened arousal and vigilance that is typical and desired for a high energy working dog. Due to the increased endogenous catecholamines there may be a competitive blockade against DM at the adrenoreceptors, negatively influencing the sedative effect (24). As a consequence of the possible competitive inhibition of catecholamines on DM, the dosage administered may need to be adjusted or the time to desired effect may differ.

Oral transmuscosal DM has a unique use in aggressive, fearful, and difficult to restrain dogs to provide sedation to facilitate safety in handling. This novel route of DM administration in dogs may be useful as a chemical restraint, sedative, premedication for general anesthesia or other clinical procedures. Prospective, randomized, controlled trials are required to explore efficacy, safety and dosages along with short- and long-term effects. CVJ