Horses present unique challenges as their temperament and size contribute to the need for sedation during periods of hospitalization, stall rest, or medical procedures. Furthermore, profound sedation is essential before anesthetic induction for the safe and reliable transition to unconsciousness. The α2-adrenergic receptor agonists produce a high degree of sedation with short durations of action (< 90 minutes) and are appropriate as sole agents for standing surgery, procedural sedation, or to facilitate anesthetic induction and recovery.1–3 However, pronounced hemodynamic effects that may occur following administration, such as vasoconstriction and reduced cardiac output, limit their usefulness in high doses.4,5
Trazodone is a unique psychotropic agent that has gained popularity in veterinary medicine, particularly in “fear-free” protocols for small animal patients. At low doses, it is a serotonin-2A receptor antagonist, while, at increasing doses, it becomes a selective serotonin reuptake inhibitor.6 Trazodone is rapidly absorbed after oral (PO) administration in horses with a peak level at approximately 1.7 hours and a terminal half-life of approximately 7 hours.7,8 At low oral doses (4 mg/kg), minimal sedation is produced whereas at high oral doses (7.5 and 10 mg/kg), adverse effects may occur and include oversedation, muscle fasciculations, and dysrhythmias.7–9
Trazodone administration (7.5 mg/kg) to normal, healthy horses decreased step frequency by 44%, suggesting its clinical utility in horses that require stall confinement for orthopedic disease processes.9 In addition, trazodone (2.5 to 10 mg/kg) administration to hospitalized horses undergoing stall confinement alleviated the behavioral effects of stress, with a decrease in stall walking, circling, or pacing, in addition to a decrease in violent behaviors.7 In horses requiring ophthalmic examination, oral trazodone (6 mg/kg) administration resulted in mild sedation 0.5 to 0.8 hours after treatment and a significant drop in intraocular pressures; excitement and excessive sweating were noted but were considered minor and self-limiting.10 While these limited data suggest that orally administered trazodone may be a valuable tool in the arsenal to treat the behavioral effects of hospitalization and stall confinement, there are no studies that quantify the sedative effects. In addition, no studies address the effects of trazodone in horses that are undergoing subsequent sedation, either for standing procedures or before anesthetic induction.
Because of its behavior-modifying properties, we hypothesized that orally administered trazodone would produce dose-dependent, clinically relevant, quantifiable sedation and reduce the amount of xylazine required for adequate procedural or preanesthetic sedation.
Methods
Animals
Eight adult mares representing various breeds (Table 1; mean, 574 ± 103 kg) were utilized. All horses were part of the University of Wisconsin School of Veterinary Medicine equine teaching herd and were determined to be healthy based on history, physical examination, and limited bloodwork (PCV/total solids). Before data collection, all horses were acclimated to the research facilities and were accustomed to handling and restraint in stocks. Hay was withheld the morning of treatment, and access to fresh water was always provided. This study was approved by the IACUC of the University of Wisconsin (V006547).
Weight, age, and breed of study subjects.
| Horse no. | Age (y) | Weight (kg) | Breed |
|---|---|---|---|
| 1 | 21 | 521 | Quarter Horse |
| 2 | 19 | 704 | Warmblood |
| 3 | 14 | 800 | Draft X |
| 4 | 16 | 454 | Arabian |
| 5 | 22 | 533 | Thoroughbred |
| 6 | 14 | 540 | Thoroughbred |
| 7 | 10 | 555 | American Saddlebred X |
| 8 | 23 | 550 | Missouri Foxtrotter |
All subjects are mares owned by the University of Wisconsin School of Veterinary Medicine and belong to the equine teaching herd.
Treatment
Horses were randomly assigned (randomization.com) to 1 of 3 groups in a blinded, crossover study design with 3 treatment groups: (1) control (no trazodone); (2) trazodone at 3 mg/kg, PO (low dose [LD]); or (3) trazodone at 6 mg/kg, PO (high dose [HD]). Treatments were separated by a minimum of 48 hours to allow a complete washout of sedative agents.
Each treatment was prepared by 1 individual (RJ) and consisted of approximately three-fourths cup of sweet feed mixed with either approximately 60 mL water (control group) or trazodone tablets that were crushed and dissolved in approximately 60 mL water (LD and HD groups; 150 mg tablets; Torrent Pharmaceuticals Ltd). Molasses (approx 15 mL) was drizzled on top of the mixture to improve palatability. The mixture was fed in a clear plastic container to ensure that the mixture was fully consumed and the treatment time was recorded. Investigators responsible for variable recordings were blinded to the treatment (WS, CS).
Data collection
Before administration of any treatments, each horse was brought from their indoor stall into the treatment room and allowed to acclimate for 10 minutes. A baseline evaluation was then performed by 2 blinded observers that consisted of measurement of heart rate (HR) via auscultation, head height above ground (HHAG; cm), and assignment of an EquiSed sedation score (Supplementary Material S1). Head height above ground measurements were assessed by visually marking the position of the ventral aspect of the chin when the horse assumed a natural resting position on a tape measure affixed to a vertical pole of the restraint stocks near the subject's head. Once baseline measurements were recorded, the treatment mixture was immediately fed, and the time of treatment was recorded (baseline [T0]). Following feed consumption, the horse was returned to its stall and left unbothered for 120 minutes. The baseline HHAG was then multiplied by 0.45 and that position was marked on the vertical bar of restraint stocks to mark the position that represented 45% of the baseline HHAG position.
After 120 minutes, the horse was walked into the treatment room, lightly restrained (halter and lead rope) in stocks, and allowed to acclimate for 10 minutes. At that time, cardiac auscultation was performed to screen for the presence of dysrhythmias; a limited ECG was performed if dysrhythmias were noted. Sedation scoring and HHAG measurement were performed and recorded (120 minutes following treatment [T120]), and the site over the left jugular was clipped and aseptically prepared. Local anesthetic (2% lidocaine, 1 mL) was injected at the venipuncture site, and an IV catheter (14-gauge, 13 cm; MILA International) was placed and secured with skin staples. Xylazine (100 mg/ml; Akorn Inc) was administered as an initial bolus (0.25 mg/kg, IV), and the horse was left unbothered for 180 seconds; a constant rate infusion of xylazine was then started (0.1 mg/kg/min, IV). Xylazine administration was discontinued when the HHAG reached 45% of baseline, and the total amount of xylazine administered was recorded. If a maximum total dose (including the initial bolus) of 1 mg/kg was given before the HHAG reached 45% of baseline, the final HHAG was recorded, and xylazine administration was discontinued. The horse was continuously observed, and parameters were reassessed every 15 to 30 minutes until HHAG returned to the level before xylazine administration (T120) at which time the horse returned to its stall.
Statistical analysis
Sedation scores and HHAG following treatment with trazodone (T120) were compared to pretreatment values (T0) for each of the 3 treatment groups. Xylazine requirements (mg/kg) for horses receiving each treatment with trazodone (HD or LD) were compared to the control group. As auscultation was performed to only screen for the presence of dysrhythmias, numerical data of HR were not analyzed. Statistical analyses were conducted using SAS software (version 9.4; SAS Institute Inc). All reported P values are 2-sided, and P < .05 was used to define statistical significance. Normality was assessed using the Shapiro-Wilk test. A linear mixed model analysis for repeated measures was used to test the treatment differences and treatment orders. Least square means and pairwise comparisons followed by Tukey-Kramer post hoc analysis were used to test for differences between treatments. Normally distributed data are presented as means ± SD.
Results
All horses completed the study. During the treatment phase, minor adverse effects noted were intermittent second-degree atrioventricular block in 2 out of 24 treatments (1 control and 1 HD) and mild, focal tremoring of the nares or muzzle in 5 out of 24 total treatments (4 LD and 1 HD).
There were no significant differences in HD or LD groups compared to control for baseline HHAG (LD, P = .31; HD, P = .97) or sedation scores (LD, P = 1.0; HD, P = .98; Table 2). The average change from T0 to T120 in sedation score was −0.25 ± 2.25, 2.63 ± 3.25, and 3.78 ± 2.8 in control, LD, and HD groups, respectively, with positive values indicating an increase in sedation. There was a significant increase in posttreatment (T120) sedation scores observed in both LD and HD trazodone groups compared to pretreatment sedation scores (LD, P = .045; HD, P = .01). The average change from T0 to T120 in HHAG measurement was −4.13 ± 4.58, −14.88 ± 11.75, and −1 .13 ± 8.31 in control, LD, and HD groups, respectively, with negative values representing a lowering of the head. Posttreatment HHAG measurements were significantly decreased (lowered toward ground) in the LD but not HD trazodone groups when compared to control horses (LD, P = .045; HD, P = .09). Xylazine requirements were increased following trazodone administration in the LD group (P = .03), with a mean increase of 0.26 ± 0.26 mg/kg compared to control (Table 3). Xylazine requirements were not significantly altered in the HD group (P = .38), with a mean increase of 0.13 ± 0.25 mg/kg compared to control. Treatment order did not impact xylazine dosage (P = .83, data not shown) or baseline HHAG measurement (P = .17, data not shown); however, baseline sedation scores were higher for horses on the second treatment day (P = .05, data not shown).
Sedation score (EquiSed score out of 18) and head height above ground (cm) measurements in study horses following control or treatment with orally administered trazodone in low-dose (LD; 3 mg/kg) or high-dose (HD; 6 mg/kg) treatment groups.
| Control | LD | HD | ||||
|---|---|---|---|---|---|---|
| Horse no. | T0 | T120 | T0 | T120 | T0 | T120 |
| 1 | ||||||
| Sedation score | 7 | 5 | 4 | 8 | 7 | 9 |
| HHAG | 118 | 117 | 129 | 118 | 120 | 106 |
| 2 | ||||||
| Sedation score | 10 | 7 | 7 | 10 | 7 | 11 |
| HHAG | 127 | 124 | 133 | 107 | 132 | 117 |
| 3 | ||||||
| Sedation score | 2 | 2 | 7 | 4 | 4 | 12 |
| HHAG | 116 | 115 | 112 | 108 | 114 | 110 |
| 4 | ||||||
| Sedation score | 6 | 8 | 9 | 10 | 5 | 10 |
| HHAG | 124 | 113 | 134 | 105 | 125 | 99 |
| 5 | ||||||
| Sedation score | 4 | 5 | 10 | 10 | 3 | 10 |
| HHAG | 120 | 118 | 125 | 97 | 113 | 107 |
| 6 | ||||||
| Sedation score | 6 | 9 | 5 | 12 | 9 | 9 |
| HHAG | 111 | 100 | 116 | 105 | 111 | 108 |
| 7 | ||||||
| Sedation score | 7 | 7 | 2 | 5 | 6 | 7 |
| HHAG | 129 | 124 | 117 | 120 | 125 | 113 |
| 8 | ||||||
| Sedation score | 8 | 5 | 6 | 12 | 7 | 11 |
| HHAG | 109 | 110 | 115 | 102 | 110 | 109 |
| Total | ||||||
| Sedation score | 6.3 ± 2.4 | 6.0 ± 2.2 | 6.3 ± 2.6 | 8.9 ± 3.0 | 6.0 ± 1.9 | 9.9 ± 1.6 |
| HHAG | 119.3 ± 7.2 | 115.1 ± 7.8 | 122.6 ± 8.7 | 107.8 ± 7.7 | 118.8 ± 8.0 | 108.6 ± 5.3 |
Total values are means ± SD.
HHAG = Head height above ground. T0 = Baseline. T120 = 120 minutes following treatment.
Total amount of xylazine (mg/kg) required for horses to reach a head height above ground measurement 45% of the baseline measurement.
| Horse no. | Control | LD | HD |
|---|---|---|---|
| 1 | 0.30 | 0.71 | 0.25 |
| 2 | 0.38 | 0.68 | 0.87 |
| 3 | 1.00 | 0.91 | 1.00 |
| 4 | 0.40 | 1.00 | 0.25 |
| 5 | 0.25 | 0.29 | 0.31 |
| 6 | 0.25 | 0.47 | 0.39 |
| 7 | 0.49 | 1.00 | 1.00 |
| 8 | 0.25 | 0.25 | 0.30 |
| Total | 0.42 ± 0.3 | 0.66 ± 0.3 | 0.54 ± 0.3 |
Total values are means ± SD.
Discussion
Despite recent advances in fear-free handling and clinical techniques, there has been limited innovation in oral sedative agents for horses, and, often out of necessity in the clinical setting, horses are typically handled using negative reinforcement and physical restraint techniques that may put both handler and patient at risk. Oral trazodone administration is an easily implementable, low-cost strategy that may improve the ease of horse handling. The current study hypothesized that orally administered trazodone would produce dose-dependent, clinically relevant, quantifiable sedation and reduce the amount of xylazine required for adequate procedural or preanesthetic sedation. Indeed, oral trazodone administration in horses resulted in a quantifiable increase in sedation and lowering of the head. Horses in the current study were safely sedated with xylazine following oral trazodone treatment with no major adverse effects noted during the study period. However, horses treated with LD trazodone demonstrated an increase in xylazine requirements to achieve a sedation level deemed adequate for anesthetic induction when compared to both the control and HD treatments.
The current study utilized the validated equine sedation scoring system EquiSed to assess sedation and tranquilization levels.11 Before the development of this scoring system, a variety of methods and systems were used separately to assess equine sedation including HHAG measurements, response to various types of stimuli (mechanical, auditory, and visual), postural instability, and the degree of ataxia.12–16 The EquiSed scoring system was developed to objectively score sedation by incorporating aspects of previous scoring systems and responses to a range of stimuli and to give a numerical score alongside HHAG. The higher the numerical sedation score and the lower the HHAG, the greater the degree of sedation. In the present study, horses treated with both LD and HD trazodone had increased EquiSed scores correlating with an increased level of sedation. Additionally, horses in the LD trazodone group had significantly lower HHAG measurements, which were associated with a greater level of sedation. These findings are consistent with other studies that have similarly reported an increased level of sedation and a decrease in associated stress behaviors in horses following treatment with trazodone.7–9 The findings in the present study provide further support for the growing body of evidence that oral trazodone may be a useful adjunct when sedating horses.
There is mounting evidence in various veterinary species, including both dogs and cats, that the perianesthetic administration of oral trazodone can reduce the minimum alveolar concentration of inhaled anesthetic required to maintain anesthesia and reduce the amount of propofol required to induce anesthesia.17–19 Interestingly, the current study found that horses treated with LD trazodone required an increased amount of xylazine to achieve the targeted reduction in HHAG compared to both the control and HD treatments. These findings are the first of their kind reported in horses treated with oral trazodone and are different from findings reported in other veterinary species, where trazodone reduces other perianesthetic agent requirements.17–19 One reason for this result could be that the current study used a 45% reduction in HHAG as the endpoint for xylazine administration. This endpoint is well described in the EquiSed scoring system, as well as in several other previous equine sedation studies.3,11 It is also notable that administration of α2-adrenergic agonists often results in relaxation lowering of the head, regardless of prior sedative treatment. Lowering of the head may not necessarily translate to readiness for a safe transition to general anesthesia and, indeed, in clinical practice, the perianesthetic assessment of the equine patient is multifactorial. It does not solely rely on the degree of reduction in HHAG but incorporates other factors such as patient temperament, patient conformation, response to stimuli, and assessor experience. This highlights that the targeted endpoint, a 45% reduction in HHAG, may have impacted the results and may not reflect the full clinical assessment of readiness for an anesthetic induction or standing procedure. For instance, a draft cross mare in the present study repeatedly demonstrated a subjective readiness for anesthetic induction based on the assessment of the authors, before the point in which 45% of the baseline HHAG was achieved. Another possibility is that, although not overtly evident, it is possible that a mild CNS excitatory effect could contribute to a greater xylazine requirement. Signs of excitement following trazodone administration have been noted in horses10; however, the impact of the effect of excitation on coadministration of other anesthetic agents has not been elucidated. Further studies using a more comprehensive endpoint are warranted to further examine the impact that trazodone treatment may have on perianesthetic xylazine requirements.
No major adverse effects were noted across all treatment groups and all horses successfully completed the study. Some horses did experience some minor, self-limiting adverse effects such as second-degree atrioventricular block and mild, focal tremoring of nares or muzzle. Of unknown significance, 1 horse became cast in the stall corner approximately 3 hours following LD trazodone treatment and 1 hour following recovery from xylazine administration. With minor manipulation to direct the head out of the corner, the mare readily stood and experienced no other adverse effects with subsequent treatments. While it is unknown if this was the result of trazodone or xylazine treatment, and despite the fact that the adverse effects following oral trazodone administration were seemingly minor and self-limiting, posttreatment monitoring may be indicated.
The current study has several limitations that warrant consideration. First, is the difficulty in properly characterizing the sedation observed following treatment with trazodone. As trazodone may be better suited for anxiolysis rather than true sedation, signs of true anxiolysis may be difficult to characterize in a group of calm horses that have not been transported to a hospital or placed in a situation that could induce stress. The EquiSed validated scoring system was utilized as a tool in the present study; however, the system has not been validated specifically for trazodone. Additionally, the mares utilized were often dull in their baseline response to blunt pressure on the coronary band. This response represented one-third of the scoring system and likely impacted the comparison between control and treatment groups. This may be the result of the subject population as the present group is part of a teaching herd and, as such, was selected for having a placid nature. Following trazodone treatment, more subtle and subjective measurements of decreased reactivity and vigilance were often present, such as softening of the eye and mouth commissures, which were not captured in the quantitative scores. A recently validated equine sedation scoring system (FaceSed) characterizes sedation based on changes in the ear position, orbital opening, and upper and lower lip position.20 Not only would this system likely capture the more subtle indicators of sedation, but changes in facial expression would likely not be affected by any potential learning effect; mares in the present study demonstrated a potential learning effect of the EquiSed system, as indicated by increased sedation scores on the second treatment day. Future studies using both the EquiSed and FaceSed systems in unison may provide a more global assessment of sedation.
Another significant limitation of the present study was breed distribution. While a variety of breeds representing varying levels of stereotypical temperaments (eg, Arabian versus draft cross) were utilized, the teaching herd at the study institution has been carefully selected to represent horses that are more compliant and are acclimated to the facility in which data collection took place. As such, the present study may not fully reflect clinical practice where patients may be fearful, young, or high strung. Finally, this study was experimental and explorative in nature, meaning the translatability and applicability of the results to clinical practice, especially regarding changes in cardiovascular or respiratory physiology, remain unknown.
In conclusion, the current study demonstrated that the oral administration of trazodone resulted in increased sedation scores with relatively minor and self-limiting adverse effects. Furthermore, it demonstrated that oral administration of LD trazodone may increase preanesthesia xylazine requirements. Additional studies in a clinical environment are warranted to determine the true significance of these results.
Acknowledgments
None reported.
Disclosures
The authors have nothing to disclose. No AI-assisted technologies were used in the generation of this manuscript.
Funding
This study was supported by a grant from the University of Wisconsin-Madison School of Veterinary Medicine Companion Animal Fund.
ORCID
Carrie Schroeder https://orcid.org/0009-0001-6791-1912
Supplementary Materials
Supplementary materials are posted online at the journal website: avmajournals.avma.org.
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