We’ve previously talked about, “Long Game” medications – those that take weeks to months for a full effect. Long Game medications are useful for persistent behavioral issues without a specific trigger, generally given daily or twice a day. These medications, like Fluoxetine and Clomipramine, are useful for a variety of behavioral issues in dogs including separation anxiety, compulsive behaviors, aggression, anxiety, and fear. They can also be useful during puppyhood when the brain is neuroplastic and medications can help to create “new positive neural connections” in puppies expressing abnormal puppy behaviors.
Game Changer Dog Behavior Medications
What are Game Changer meds? These are drugs with (relatively) rapid onset and (relatively) short duration. Game Changers are useful when the stimulus is known, predictable, avoidable, and time limited. Game Changer medications are generally not helpful when the trigger is unknown, not avoidable, unpredictable, unlimited, and the medication has not been previously tested on your dog[1]. The latter point deserves emphasis. We know that any time you alter neurotransmission there is the potential for behavior to get worse, get better, or stay the same, therefore It is advised to try/test the medication during times of calm to assess the effect and observe for any adverse side effects. Using a medication for the first time during a “behavioral crisis” is generally a bad idea because you don’t know how the dog will react to the drug.
When to Use Game Changers
These medications can be useful in a variety of situations:
- When the behavioral trigger is known and we are aware that it is going to happen. Probably the best example is noise phobias – particularly fireworks and thunderstorms – we know they are coming and we can premedicate our dogs before the event. In a perfect world, this results in the dog being less anxious and calmer.
- Prior to a stressful event – these include veterinary visits and grooming. Making the stressful visit less stressful is good for the dog, the human, and the veterinary or grooming staff.
- Prior to a stressful event for dog to human aggression – prior to veterinary treatment protects the veterinary staff as well as the dog.
- Game Changer medications can be useful in combinations given the night before and the day of a stressful event.
- Since we know that Long Game meds take time to take effect, Game Changer meds can be used “as a bridge” while the long game meds take effect. The calming effects of the Game Changer will be present while waiting for the Long Game med to take effect, this is particularly important for the dog’s humans who may be at their wits end.
- They can also be used in conjunction with long term medications, either as a “situational med” or an added long-term med[1].
Are Game Changer Meds Dog-Approved?
Almost all of the Game Changer meds are human drugs “adopted” for use in dogs. As in previous “Dazzled” articles, we will be reviewing the peer reviewed literature. The caveat is that there is very little financial (or other) incentive for drug companies to do the work to get these game changer medications FDA approved for behavioral issues in dogs. Most of these medications are off patent, available as generics, and inexpensive. The exception is the FDA gel product, Sileo (dexmedetomidine oromucosal), which is approved for noise phobia in dogs (“SILEO is indicated for the treatment of noise aversion in dogs[2].” We will start with the most commonly used Game Changers used for behavioral issues in dogs, and come back to Sileo later.
Use of Human Drugs in Dogs
It is useful to remember that medications approved for use in humans can be used for behavioral issues in dogs provided the ELDU (Extra-Label Drug Use) and AMDUCA (Animal Medicinal Drug Use Clarification Act) rules are followed [3]. For more information see Dazzled by Science Part 5.
It is also important to note that because these drugs are not approved for use in dogs, there are no “larger” clinical trials required for FDA approval, thus in the available studies the sample size is often small, and the studies may not be considered “rigorous.” So how is it that, without “good science,” we can use these human drugs for dogs with anxiety, phobia, panic, aggression, compulsive behavior, veterinary-related fear, anxiety, stress, postoperative confinement and travel?
We know from the human literature the (presumed) mechanism of action, the clinical behavioral, mental health, and adverse effects, and the efficacy of the medications. Just as important we know from veterinary clinical experience, both general practice DVMs and Veterinary Behaviorists, that the Game Changer meds can influence canine behavior and have a role in the behavior tool box.
Art and Science
Now, of course, this doesn’t mean that all dogs have a positive response to Game Changer meds or that these meds are without side effects – but the art of veterinary behavioral practice is to choose a medication based on experience and training, the needs of the specific patient, the dog’s behavioral issues, and the family resources, and then to assess the efficacy. Once trialed, based on re-assessment, the medication can be increased, decreased, discontinued, additional medication may be added, and/or the behavior modification program adjusted.
There is no one-size-fits-all road map when using behavior medications. There are often comments that behavior vets rarely use trazodone, suggesting that the use is inappropriate. It is most likely that by the time the dog gets to the behavior veterinarian, that drug has been trialed and not been successful. Many general practice DVMs are very familiar with the use of trazodone in canine behavior cases.
Which are the Game Changer Medications?
Game Changer Dog Behavior Medications include:
- Trazodone
- Gabapentin
- Clonidine
- Short-acting benzodiazepines (alprazolam, valium, midazolam).
Although vilified by some, acepromazine can also be useful as a Game Changer in some situations (we will cover that later). Melatonin, a naturally occurring supplement, has use in some game changer combos, but as a supplement, not a drug, it will not be covered here. Less commonly used game changers include propranolol and pregabalin.
TRAZODONE
Next to gabapentin, Trazodone is likely the most commonly used behavioral medication in veterinary medicine. Many general practice veterinarians are familiar with it. Trazodone was developed in Italy in the 1960s. The FDA approved Trazodone for the treatment of depression in humans in 1981. Trazodone is a serotonin (5HT) antagonist and reuptake inhibitor (SARI). It blocks the serotonin 2A and 2C receptors and inhibits the serotonin transporter; this means that the concentration of serotonin in the synaptic space is increased[4]. Interestingly, the effect of trazodone on 5HT is dose dependent – at low doses 5HT 2A and 2C receptors are blocked and at higher doses the serotonin transporter is inhibited. Trazodone also antagonizes the H1 histaminergic and alpha1 adrenergic receptors leading to a hypnotic effect. Trazodone is the only widely used SARI in veterinary medicine, and is used clinically for activity restriction (post-surgery), and to ameliorate stress, anxiety, and fear associated with hospitalization, transportation, veterinary visits, and noise phobia.
And so, we have an extremely commonly used drug for various dog behavioral issues and the first question we should ask is, “Does it work?” and the answer is, “maybe and it’s complicated.” As we have previously alluded to, studies on the impact of medications on canine behavior are often complicated by small sample size, lack of placebo control, variety of drug dosage, use of owner reports, investigator bias, concurrent use of multiple medications, variability of behavioral issues, lack of validated behavioral ethograms, various definitions and expressions of fear, anxiety and stress depending on environment and current situation.
Strengths and Weaknesses of the Studies
In 2023 Dillon published a Knowledge Summary: “The efficacy of trazodone in reducing stress related behaviors in hospitalized dogs or dogs confined post-surgery” in Veterinary Evidence [5]. They critically analyzed three studies to answer the question: “In hospitalized dogs or dogs confined post-surgery, does administration of trazodone reduce stress related behaviors compared to no treatment with trazodone?” The goal was to evaluate the strengths and weaknesses of the literature and determine the strength of evidence that trazodone is useful to reduce stress in hospitalization or post-operative confinement. They concluded that the evidence for the use of trazodone in these situations is “weak: The available evidence weakly supports the hypothesis that administration of trazodone is an effective treatment in reducing stress related behaviors in hospitalized dogs and dogs confined post-surgery, and further studies are required to confirm its efficacy. The quality of the evidence when hospitalized dogs were studied was moderate (Gilbert-Gregory et al., 2016), however in dogs studied that were confined post-surgery, the evidence is weaker (Gruen et al., 2014; Gruen et al., 2017)[5].” [6-8].
This is an excellent and thorough review of the three studies looking at the effect of trazodone on stress associated with hospitalization and post-operative confinement. The review is open access and well worth a look if you are into the specifics of assessing strength of evidence.
So, what does that mean for your dog? Maybe nothing – like many small studies looking at behavioral effects of medication in dogs these studies are “muddied” by multiple confounding factors. We do know from these studies that the drug appears to be safe with minimal adverse or serious side effects. We can choose to believe, based on our knowledge of the mechanism of action and studies in other species, that trazodone can be efficacious in some dogs with some behavioral issues.
Confounding Factors in Evaluation of Medications in Veterinary Medicine
While our original plan with Dazzled by Science – behavior medications, was to only review and include peer- reviewed studies testing one medication, this has proven to be difficult, as many dogs in many of the studies have been on multiple medications.
Gruen and Sherman [9] evaluated the effect of trazodone as an adjunct medication on anxiety (generalized, separation, and travel anxiety) or phobic disorders (storm, noise, combination phobia) in client-owned dogs referred to the behavior clinic from 1995 to 2007. This was a retrospective record review including 56 dogs already on either fluoxetine or clomipramine. Owners were given an individually tailored behavioral management program. When the Long Game medication was “insufficient,” trazodone, at variable dosage schedules, was added to either a SSRI or TCA. “The decision to begin trazodone administration was based on the joint assessment of the clinician and client.” Interpretation of the effect of a single drug in a retrospective study is complicated by the other medications, effect of time, various diagnoses, and variable follow up time. Adverse reactions were uncommon and self-limiting. Outcome was assessed by comments recorded in the record of 70% of the dogs included (n=40). After adding trazodone 29 dogs were considered “very improved” and 5 “somewhat improved.” Criteria for improvement was not included.
Trazodone in Shelter Dogs
Dogs in animal shelters are subject to uncontrollable and unalterable stressors. Abrams et al. [10] chose to evaluate the effect of trazodone in relieving transitional stress and the accompanying immunosuppression of dogs admitted to a shelter. The aims were to determine if the administration of trazodone would
- Reduce the prevalence of canine infectious respiratory disease complex in the shelter
- Reduce length of stay, and
- Increase the percentage of live outcomes (adoptions) while decreasing the percentage of euthanasia.
Records of 1766 dogs from an open admission animal shelter, which was a combination municipal shelter and 501C3, were reviewed. The idea behind the study was that transitional stress could be decreased by a dose of trazodone (in food) on admission to the shelter. The original plan was to repeat the dose on day 2, however complications of a large open admission shelter made this often impossible and they ended up with three trazodone groups:
- Ideal = per protocol, 1 dose on admission and 2nd the next morning
- Delayed first dose, but 2 doses in the first 48 hours
- Single dose only
Dogs included in analysis had a length of stay of at least 4 days and were divided into two groups, “Trazodone” and “No Trazodone”. The study took place in two locations in November and December of 2016, 2017, and 2018. Dogs in the No Trazodone groups were from 2016 and 2017 and the Trazodone group from 2018. Kudos to these authors, as this study highlights the difficulty of doing clinical studies in chaotic situations where the investigators have little control.
In the end there were 1357 dogs in the No Trazodone group (747 from 2016 and 610 from 2017) and 409 in the Trazodone group. Although they describe no statistical difference in the various trazodone groups, they chose to exclude 163 dogs that did not receive 1 dose within 24 hours or 2 doses within 48 hours. The No Trazodone treatment group was stratified by year and shelter and these subgroups were compared. No differences were found and the data were combined.
An increased percentage of sick dogs (canine infectious respiratory disease complex) was observed in the No Trazodone group (41%) compared with the Trazodone treatment group (29%), and the increased percent of sick dogs in the No Trazodone group accounted for longer length of stay. The percent of dogs adopted in the No Trazodone group was 30.4%, compared with 42.1% for the Trazodone group.
This was a monumental effort resulting in correlations suggesting Trazodone may be beneficial in decreasing transitional stress in a shelter environment. The authors suggest that Trazodone does not affect sick dogs but appears to decrease sickness resulting in shorter length of stay and increased adoption. Percent of dogs euthanized was not different between the two groups. While imperfect, the authors adapted to the ever-changing environment and describe some interesting correlations. Trazodone may decrease stress associated with shelter admission, decrease incidence of respiratory disease and length of stay. Since trazodone is inexpensive with few serious side effects in the majority of dogs, use on shelter admission may be a viable option.
Trazodone and the Veterinary Visit
Kim et al [11] designed a randomized double-blind placebo-controlled crossover clinical trial to test the hypothesis that a single dose of trazodone 90 minutes before driving to the veterinary hospital would reduce behavioral and physiologic signs of stress in the dogs, and owner stress, during veterinary visits. Stress was assessed by questionnaires, behavioral observations, video assessment, and physiologic measurements including respiratory rate, heart rate, heart rate variability, and serum cortisol. Dogs enrolled in the study were clinically normal, with a history of stress and anxiety during veterinary visits, and were accustomed to wearing a harness (for heart rate monitoring). Two structured visits were completed one week apart and dogs were randomly assigned to get trazodone or placebo at the first visit. It is worth noting that these were “simulated” veterinary visits that occurred on the weekend and “barking dog sounds were played from a mobile device, and one of the investigators walked around the room with stuffed toy dogs every 5 minutes.”
Clients assessed their dog’s and their own stress level pre-appointment at home, during transport, and during the examination using a 5-point Likert scale (1=very low to 5=very high) to answer questions such as, “Rate YOUR DOG’s stress level during the process of getting your dog into the car.” Owners were also asked to identify which visit they thought that their dog received Trazodone. The investigator evaluated the dog’s behavior for both visits focusing on aggressive behavior, sedation and compliance.
- Sedation was assessed at 3 time points
- Aggression at 7 time points
- Compliance at 4 time points.
- Video recordings were assessed at 9 time points when the dog was in the exam room [12, Supplementary Appendix S4.]
Body language (body posture, tail posture, ears, mouth, vocalization, and activity (defensive and avoidant behavior) combined into a “global stress level” from 1 = “relaxed” to 5= “extremely stressed.”
Twenty dogs (10 NM & 10 SF) were included in the study, two of which were on Fluoxetine.
Mean dog stress score, as assessed by the owner during their dog’s physical examination, was significantly lower for dogs receiving Trazodone compared with placebo (3.5 ± 1.0 vs 4.2 ± 0.8; p=0.005). No significant differences were identified during time in the waiting, examination, or treatment rooms. While reported owner stress was not different between the visits, 18 of 20 owners correctly identified the day the dog received trazodone. There were no significant differences in aggressive behavior, sedation and compliance between dogs that received Trazodone and placebo.
The mean stress score from video analysis “before the visit” was significantly (p< 0.001) lower for dogs that received Trazodone (1.64 ± 0.83) versus placebo (1.75 ± 0.91). I interpret “before the visit” to refer to the three 15 second time points (T1-T3) before the physical examination, however, this is not clear in the manuscript. When compared to during the physical exam (T4-T9), mean stress scores were lower before physical examination ( T1-T3) in both dogs that received Trazodone and placebo. Cohen’s kappa showed only fair inter-rater reliability. Heart rate was increased, while respiratory rate and heart rate variability were decreased in dogs receiving Trazodone compared to placebo. There was no significant difference in serum cortisol concentration in dogs that received trazodone, compared with placebo (3.56 ± 2.54 µg/dL vs. 3.40 ± 2.11 µg/dL).
The authors conclude “based on owner assessments, video observation analysis, and components of heart rate variability, we found that oral administration of Trazodone 90 minutes prior to transport to a veterinary clinic led to a significant reduction in stress-related behaviors and physiology.” Frankly I don’t know what “a significant reduction in physiology” means. Unfortunately, this is one of those studies where they try to do everything and end up with not so much. The design is overly complicated making it difficult to ferret out the pertinent or important information. Some things were assessed at 7 time points, some at 3, some at 4 with no explanation of why these time points were chosen. A timeline would have been useful to better explain the study. One has to assume that samples for serum cortisol were obtained when the dog was taken without the owner to the treatment room for blood collection. At the time of this study, salivary samples were frequently used to measure cortisol, and dogs can be easily accustomed to the procedure, this would have allowed more robust cortisol sampling which could have provided more information.
When dogs received Trazodone, heart rate was significantly increased (and respiratory rate and measures of heart rate variability were decreased). This is interesting because many studies in dogs and humans describe “sympathetic bradycardia” following Trazodone. The authors state that the increase in heart rate is “consistent with findings in a previous study,” however, the study cited reported tachycardia with intravenous trazodone, not oral trazodone.
They videotaped behavior but the only “fair” inter-rater reliability (different observers identifying the same behavior the same), calls into question the validity of the video assessment of behavior. One would expect a much higher degree of agreement with observers trained to assess behavior.
This was an ambitious study which could have been enhanced by focusing on behavior, reported by both owners and investigators, and videotaped assessment of behavior, and providing a clear visual description of the timeline. While there was a significant difference in the stress score of dogs receiving Trazodone compared to placebo during the physical examination (but not at other times), one needs to remember these are client reported Likert scale scores where the subjective view of a “3” or “4” rating may vary between individuals. The overall lack of difference in a variety of parameters between dogs receiving Trazodone and those same dogs receiving placebo does not suggest a robust effect of a single dose of Trazodone 90 minutes before transport on stress in dogs in this scenario. There were few side effects reported.
The Bottom Line on Trazodone
The peer reviewed science is not robust but does suggest that trazodone can be useful for a variety of behavioral issues in dogs. It has found use in situations with known predictable triggers, as an adjunct during long-term medication absorption and in combination with other behavioral medications.
Next time we will cover Gabapentin – the most utilized medication in both human and veterinary medicine.
Thanks to Rene Smith CBDC, Kerrie Hoar MS, CDBC, CPDT-KA, Michael Shikashio CDBC and C.C. Bourgeois CPDT-KA, CSAT, PMCT for careful review of this article. This article covers the peer reviewed case controlled and retrospective studies as of 8/1/2024. I alone am responsible for any errors.
[1] E’Lise Christensen https://behaviorvetsnyc.com/event/game-changer-medications-trazodone-gabapentin-clonidine-benzodiazepines/ May 2022
[2] https://www.zoetisus.com/content/_assets/docs/Petcare/sileo/sileo-pi.pdf
[3] https://aggressivedog.com/2023/06/19/dazzled-by-science-part-5-behavior-medication/
[4] Crowell-Davis SL, Murray TF, de Souza Dantas LM. Veterinary Psychopharmacology. Wiley & Sons, Inc. 2019.
[5] Dillon L. The efficacy of trazodone in reducing stress related behaviours in hospitalised dogs or dogs confined post-surgery. Veterinary Evidence (2023) 8 :1 -20, 2023 DOI: https://doi.org/10.18849/ve.v8i2.550
[6] Gilbert-Gregory SE, et al. Effects of trazodone on behavioral signs of stress in hospitalized dogs. J Am Vet Med Assn. 2016:249, 1281–1291. DOI: https://doi.org/10.2460/javma.249.11.1281
[7] Gruen ME, et al. Use of trazodone to facilitate postsurgical confinement in dogs. J Am Vet Med Assn. 2014:245, 296–301. DOI: https://doi.org/10.2460/javma.245.3.296
[8] Gruen ME, et al. The use of trazodone to facilitate calm behavior after elective orthopedic surgery in dogs: Results and lessons learned from a clinical trial. Vet Behav. 2017:22, 41–45. DOI: https://doi.org/10.1016/j.jveb.2017.09.008
[9] Gruen ME, Sherman BA. Use of trazodone as an adjunctive agent in the treatment of canine anxiety disorders: 56 cases (1995-2007). J Am Vet Med Assn. 2008: 233:1902–1907. DOI: https://avmajournals.avma.org/view/journals/javma/233/12/javma.233.12.1902.xml
[10] Abrams J, et al. Trazodone as a mediator of transitional stress in a shelter: Effects on illness, length of stay, and outcome. J Vet Behav 36:13-18, 2020. DOI: https://doi.org/10.1016/j.jveb.2020.01.001
[11] Kim S-A, et al. Effects of trazodone on behavioral and physiological signs of stress in dogs during veterinary visits: a randomized double-blind placebo-controlled crossover clinical trial. J Am Vet Med Assn. 260:876-883, 2022. https://avmajournals.avma.org/view/journals/javma/260/8/javma.20.10.0547.xml
[12] Supplementary table 4 https://avmajournals.avma.org/view/journals/javma/260/8/javma.20.10.0547.xml?tab_body=supplementary-materials
https://www.cliniciansbrief.com/article/chill-protocol-manage-aggressive-fearful-dogs
https://todaysveterinarynurse.com/behavior/benefits-of-medicating-patients-for-veterinary-visits/
Lana Kaiser, MD, DVM
Lana Kaiser MD, DVM, born in Buffalo, NY, received a BA in English from SUNY at Buffalo with plans to be a poet. She is a graduate of Michigan State College of Human Medicine and College of Veterinary Medicine. She is a Board-Certified (human Internist), a cattle veterinarian, and a Michigan State University Emeritus Professor.
Trained as a biomedical researcher with a research focus on cardiovascular pathophysiology and parasitology, she is also interested in scientifically studying the interaction between humans and animals, and has published in both scientific disciplines. She resides on a farm in Mason, MI where she raises Maine-Anjou and Red Angus cattle.
She has a mobile beef cattle practice, consults for several national agricultural entities, and has written and lectured about animal welfare, animal health, genetic defects, human-livestock interactions, and animal behavior at the state and national levels. She is involved in issues of animal behavior and welfare at the county, state and national level. Although she has a long history of training dogs, she “stumbled into” the “contemporary dog industry” by attending the first Aggression in Dogs Conference, which was followed by the master course, and innumerable other dog behavior and training webinars and conferences. When she started her dog behavior journey she had six dogs, an ancient Belgian Tervuren), an almost ancient Pyrenees, a very very ancient OCD deaf Beagle and three puppies - two Pyrenees and a Tervuren. She currently shares her life with an adult Belgian Tervuren, an adult Pyrenees, a Pyrenees puppy, a herd of cows and one horse.
