Healthy client owned exclusively indoor cats between 2–12 years of age with a history of anxiety during transport or veterinary examination. Cats were required to have ≥ 1 behavioural sign consistent with transport- or veterinary examination-associated anxiety. 

Three castrated males and seven spayed females qualified for and completed the study with a mean age of 6.8 years (range 2.1 to 10.7 years) and a mean body weight of 4.6 kg (range 3.3 to 6.5 kg).

All cats were reported by their owners to have had at least one of the evaluated signs of anxiety during transport in a carrier in the past. Eight cats were reported by their owners to have had at least one of the evaluated signs of anxiety during veterinary examination in the past.

Of 13 cats, 10 completed the trial—two cats were withdrawn due to illness unrelated to the study protocol and another was withdrawn by the owner after reporting a suspected adverse effect to the trazodone administration.

• Each cat was assigned to first receive a single dose of 50 mg trazodone hydrochloride or a placebo (a sodium bicarbonate tablet identical in appearance to trazodone) by mouth. A randomisation table was used to establish which cat received which treatment first and after a 1–3-week washout period each cat received the opposite treatment.
• Owners were instructed to orally administer the randomly assigned treatment (placebo or 50mg trazodone hydrochloride) in a manner that would be best tolerated by their cat as decided by each cat’s respective owner. Treatment was provided to 4 cats in malleable treats, to 4 cats hidden in canned food, and to 2 cats by direct administration by hand. All owners reported that their cats received the total amount of the medication.
• Trazodone doses ranged from 7.7–15.2 mg/kg.
• The duration between treatment administration at home and placement of the cat into the travel carrier was 1–1.5 hours.
• Owners lived within a 10–30-minute drive of the veterinary
• After a brief wait in the lobby (~1.5–2 hours post treatment administration) the cat and owner were escorted to a designated examination room.
• The cat carrier was placed on the floor and the door opened to allow the cat to voluntarily exit. If the cat exited voluntarily, it was then allowed to explore the room briefly then placed on the examination table. If the cat did not exit voluntarily the carrier was placed on the examination table, the top removed, and the cat was gently lifted onto the table. If the carrier top could not be removed the cat was gently extracted from the carrier and placed on the examination table.
• An identical physical examination was performed on each cat by the same veterinarian and assisted by the same technician in the owner’s presence throughout the study. The owners, veterinarian, and technician were all blinded to which treatment had been administered to each cat.
• The physical examination consisted of 12 procedures typically completed within 20 minutes and in the same order. This involved removal of the cat from the carrier; placement on the examination table; weighing on a tabletop scale; visual examination of the head, eyes, and oral cavity without instrumentation; thoracic auscultation and measurement of heart and respiratory rates; abdominal palpation; lymph node palpation; measurement of aural temperature; direct ophthalmoscopic examination; otoscopic examination; shaving of a small section of hair at base of tail and Doppler ultrasonographic determination of arterial blood pressure; and release after examination.
• The physical examination concluded ~2–2.5 hours post treatment administration.

Double blind, placebo-controlled, randomised crossover study.

3 scoring systems were used to assess for signs of anxiety and fear at specific points: the McCune cat stress score (CSS), the tractability score, and the behavioural response score.

Owners used a standard form to assign cumulative stress scores to their cat at the following points: before transport, during transport, and after transport, while in the clinic waiting room, during the examination, and immediately after the examination.

Objective assessments:

• Owners were asked to report for each assessment point the presence or absence of objective signs associated with anxiety, including urination, defaecation, anal gland release, vomiting, excessive salivation, trembling, open-mouth breathing, and vocalisation.
• Physiological data was collected by the veterinarian during the examination including heart rate, respiratory rate, aural temperature, and Doppler ultrasonographic measurement of arterial blood pressure.

Subjective assessments:

• Intensity of vocalisation was scored (0 = absent, 1 = mild, 2 = moderate, and 3 = severe) by the owner at each assessment point.
• Behavioural data following each of the 12 procedures and for the examination overall were assigned by the veterinarian by use of the behavioural response score system^. (0 = absent, 1 = mild, 2 = moderate, 3 = severe, and 4 = too severe to complete), which involved scoring 4 specific cat behaviours at each assessment point: vocalisation (whimper, cry, or meow), struggling or attempts to escape, aggression (except for hissing or growling; ears flattened back, tail lash, or batting), and severe aggression (biting, attacking, and hissing and growling).
• The veterinarian assigned a cumulative stress score for the entire examination (1 = fully relaxed, 2 = weakly relaxed, 3 = weakly tense, 4 = very tense, 5 = fearful or stiff, 6 = very fearful, and 7 = terrorised).
• At the conclusion of the veterinary examination, both the veterinarian and owner independently assigned a tractability score, which was based on the ease by which the veterinarian could perform each examination procedure and the appearance of the cat (0 = cat completely relaxed, 1 = easy to examine but not entirely relaxed, 2 = relatively easy to examine, 3 = restraint needed to examine safely, 4 = very difficult to examine, and 5 = unable to examine).
• At the conclusion of each visit and to understand owner perception of their cat's anxious behaviour, owners were asked to speculate whether their cat received the placebo or trazodone.

After each visit, in a survey sent via email, owners were asked to report any adverse events noted within 24 hours after administration of the assigned treatment (placebo or 50mg trazodone hydrochloride).

Owner assessment:

• After receiving either treatment no cats had any of the evaluated signs of anxiety. Stress scores assigned before transport (after treatment administration 1 to 1.5 hours earlier) were significantly lower for trazodone than for the placebo (McNemar test, P = 0.02)
• During transport, 3 cats had 1 or more of the evaluated signs of anxiety. One cat urinated and defaecated after receiving the placebo and urinated after receiving trazodone. The second cat vomited, had hypersalivation, trembled, and breathed with an open mouth after receiving the placebo. The third had open mouth breathing after receiving the placebo. Stress scores assigned during transport did not differ significantly between treatments.
• After transport while in the waiting room, no cats had any evaluated sign of anxiety after receiving trazodone; however, 1 cat urinated, defaecated, excessively salivated, and had open mouth breathing and another cat excessively salivated after receiving the placebo. Trazodone administration resulted in significantly (McNemar test, P = 0.02) lower cat stress scores at this assessment point than did placebo administration.
• 10 cats vocalised before transport when given the placebo, and 7 cats vocalised when given trazodone; all except 1 cat had a reduction in their vocalisation intensity score. Trazodone administration resulted in significantly (Wilcoxon signed rank test, P = 0.008) less frequent vocalisation during transport than did placebo administration. 8 cats vocalised after transport when given the placebo, and 2 vocalised when given trazodone.
• During the veterinary examination, no cats urinated, defaecated, released their anal glands, vomited, excessively salivated, trembled, or had open-mouth breathing, regardless of treatment received. No cats vocalised. Trazodone administration resulted in significantly (Wilcoxon signed rank test, P = 0.04) lower stress scores during this period than did placebo administration. Owner-assigned tractability scores during the examination were significantly (P = 0.03) more favourable with trazodone versus the placebo.
• After the veterinary examination, no cats urinated, defaecated, released their anal glands, vomited, excessively salivated, trembled, or had open-mouth breathing, regardless of treatment received. Trazodone administration resulted in significantly (Wilcoxon signed rank test, P = 0.008) lower stress scores during this period than did placebo administration.
• Although blinded to treatment, 9 of 10 owners correctly identified the treatment their cats received after observing their behaviour during transport and examination.

Veterinary assessment:

• All physiologic values for all cats were within reference ranges after trazodone and placebo administration. No significant differences were identified between trazodone and placebo with respect to heart rate (P = 0.55), blood pressure (P = 0.91), or aural temperature (P = 0.24). Respiratory rate was lower, albeit nonsignificantly (P = 0.055), after trazodone versus placebo administration.
• Overall, behavioural scores as assigned by the veterinarian were significantly (Wilcoxon signed rank test, P = 0.006) lower for cats after receiving trazodone versus the placebo. Trazodone administration resulted in significantly (Wilcoxon signed rank test, P = 0.01) more favourable tractability scores than did placebo administration, with cats considered relaxed versus tense after receiving trazodone. For all components of the veterinary examination, trazodone administration resulted in significantly (McNemar test, P = 0.03 for each comparison) lower stress scores before, during, and after veterinary examination.

Adverse events:

• In response to the email survey after the veterinary visit, owner reports of adverse events were limited to 1 report of transient sleepiness (in addition to the one cat that was withdrawn by the owner from the study due to agitation and vocalisation 30 minutes post trazodone administration).
• One cat was scored as fearful when given the placebo and very fearful (a worse score) when given trazodone. Because anxious cats without treatment may be fearful or very fearful for veterinary visits, this particular cat's behaviour may have represented a lack of response to trazodone or a paradoxical response.

• There is no calculated sample size. The use of sample size calculation directly influences research findings. Very small samples undermine the internal and external validity of a study. Very large samples tend to transform small differences into statistically significant differences—even when they are clinically insignificant. As a result, both researchers and clinicians are misguided, which may lead to failure in treatment decisions.
• Small sample size: only 10 cats completed the study. A small sample size reduces the significance and undermines the validity of the study because the results are less representative of the entire population and there is a higher margin of error.
• Large variability in sample population in terms of breed, age, entire vs neutered, home environment, and sex. This is due to the absence of clear inclusion and exclusion criteria leading to a broad range of eligible cats.
• Variability in method of treatment administration resulting in different levels of stress imposed on each cat in treats, in canned food, and by manual administration. In addition, the presence of food in the upper gastrointestinal tract in some cats and not others lead to variability of the time taken for absorption of the trazodone into the blood.
• Variability in the duration of time from administration of treatment to placing the cat in the carrier (1 to 1.5 hours) and variability in the length of time the cat is transported (10 to 30 minutes). This results in variability of time from administration of treatment to time of the physical examination being carried out by the veterinarian (1.5 to 2 hours) and therefore absorption levels at each assessment point will have varied between cats.
• Lack of journey detail included—quiet vs busy roads, frequent starting and stopping, the position of the carrier in the car (back seat, footwell, in the boot etc.). Variability in these factors could impact levels of stress endured by the cat while being transported.
• Variability in doses used per kg trazodone doses ranged from 7.7 to 15.2 mg/kg.
• Variability in how cats exited the carrier; some exited on their own, others were removed via removing the top of the carrier and others were extracted from the carrier via the door resulting in different levels of stress imposed on the cat depending on which method was used.
• Variability in the washout period was between 1 to 3 weeks.
• Mostly subjective scoring was used, especially by the owners. Objective scoring by owners did not involve measurement of physiological signs of anxiety such as heart rate or respiratory rate. These were only assessed by the veterinarian in the clinic and so there is no data for these parameters at other assessment points.
• Owners may have given higher scores on the subjective assessments if they were stressed themselves.
• None of the scoring systems used are validated.
• The McCune cat stress score has been regarded as a static and subjective measurement of behaviours displayed over the short term. It has extensively been used to evaluate the level of welfare for cats in shelters. However, it has been found that the CSS might not clearly correlate with physiological stress, as seen by difficulties to validate the scores, but it may be an indication of coping with environmental challenges in cats.
• The study does not explore the effects of other doses of trazodone, only 50 mg.
• Lack of reported detail within the veterinary clinic such as how many other people/animals there are in the lobby (i.e. how busy), how loud it is, what species of animals are present, the size of the other animals etc. as this could contribute to stress levels experienced by the cat.
• Type of carrier is not specified. Details such as size of carrier compared to cat and whether a blanket was used to protect from visual stimuli.
• Information on where the carrier was placed is not included, i.e. on the floor with potential olfactory stressors or on the owner’s lap, on a table etc.

Purpose bred, neutered male, domestic shorthair laboratory cats aged 6 months (1 cat) to 3–5 years old (5 cats). Cat weights ranged from 3 kg to 4.7 kg.

The five adult cats had previously been used as control subjects for a separate study where they had been conditioned to entering a carrier voluntarily. The 6-month-old cat had not received any prior conditioning.

6 cats.

• Each cat was kept in identical wire enclosures of the same dimensions containing the same items in the same room within a laboratory facility and were kept on a 12/12 hour light/dark cycle.
• Each cat was fed Hill’s™ Science Diet™ Adult Light two times daily and maintained at an ideal body condition score (5/9) based on the Purina® Body Condition System.
• Prior to enrollment each cat received a physical examination, chemistry panel, complete blood count, and urinalysis. After the study, these tests were repeated to rule out any changes attributable to administration of trazodone.
• Cats were administered treatments over a 4-week period. A 50 mg trazodone tablet (range: 10.6–16.7 mg/kg) was given as the first treatment and 75 mg trazodone tablet (range: 16.0–25 mg/kg) as the second treatment. These treatments were not randomised and so the data obtained has not been statistically analysed or evaluated as part of this summary. The third and fourth treatments were randomised to either the 100 mg trazodone tablet (range: 21.3–33.3 mg/kg doses) or placebo (treats or food with no tablet).
• The washout period between treatment days was 4–7 days.
• Trazodone tablets were quartered and hidden in a tablespoon of Hill’s™ Prescription Diet a/d or Pill Pockets™.
• On days when treatment was administered the cats were fed a reduced portion (1/8 cup) approximately 3 hours before treatment.
• Examinations consisted of the following and were carried out 90 minutes after treatment administration:
  
  
  • A carrier was placed outside the enclosure door, which was opened, and the cat was allowed to enter voluntarily, with the incentive of a treat or if refusing was gently picked up and placed in the carrier.
  • The cat was then carried to the examination room (35 m down the hall) and the carrier was placed on an examination table. The cats were allowed to exit voluntarily or removed from the carrier via removal of the top. If resistant to removal they were left in place.
  • Each physical examination was performed in the same order: cardiac and pulmonary auscultation followed by peripheral lymph node palpation, abdominal palpation, otoscopic examination, ophthalmoscopic examination, oral examination, mock jugular venepuncture in a sternal position and mock cystocentesis performed in lateral recumbency.
  • All cats were handled with minimal restraint using a towel or technician assistance if necessary. Treats were given to all cats to encourage compliance. If a cat became too fractious, the examination was concluded.
  • Each cat was given the chance to enter the carrier voluntarily before being returned to their enclosure.

Blinded placebo controlled randomised crossover study.

Objective assessments:

• Accelerometer activity monitors: Each cat was fitted with a pre-equilibrated activity monitor attached to its collar to record locomotor activity. The monitor was applied 1 week prior to the study to allow a period of acclimation to the device. The monitor was worn, and data was collected for the 4-week duration of the study and monitors were set to record at intervals of 30 seconds.
• Physiological parameters: heart rate and respiratory rate were recorded during the veterinary examination.

Subjective assessments:

• Activity observations: Focal observation samples of the cats’ activity in their enclosures were recorded by a handheld digital video camera prior to treatment administration and every 30 minutes for 4 hours after. Each cat was given an enclosure activity score from 1 (sedate) to 5 (very active) for each time interval.
• Behavioural response to examination: This was performed for each cat for each treatment. All examinations and behavioural ratings were performed by an investigator masked to treatment. No information can be found on the validity of this scoring system.
• McCune cat stress score:  Cats were assessed at three time points: while in their carriers prior to the examination (pre-examination), out of the carrier during the examination (examination), and in their carrier after examination (post-examination). These scores were combined for an overall stress score. This was performed for each cat for each treatment.

• Accelerometer data revealed that cats were less active after receiving 100 mg trazodone tablet compared to the placebo with peak sedation occurring 2.5 hours post administration.
• Enclosure activity scores of 1 (‘sedate’) and 2 (‘calm’) were only observed in cats when they received trazodone (at any of the doses) with 4/6 of the cats having a more than two-point reduction in their scores after being given a 100 mg dose. There was a statistically significant difference between the enclosure activity scores of cats when they received trazodone 100 mg compared with placebo (Fisher’s exact test, n = 12; P = 0.06).
• Total behavioural response scores given for each cat reflected only struggling, aggression and vocalisation. The scores revealed no significant difference between cats that received trazodone 100 mg and placebo (Wilcoxon signed rank test, n = 6; P = 0.594).
• There was no difference between the 100 mg trazodone and placebo groups for the overall stress scores recorded before, during and after the examinations (Wilcoxon signed rank test, n = 6; P = 1.000).

• There is no calculated sample size. The use of sample size calculation directly influences research findings. Very small samples undermine the internal and external validity of a study. Very large samples tend to transform small differences into statistically significant differences—even when they are clinically insignificant. As a result, both researchers and clinicians are misguided, which may lead to failure in treatment decisions.
• Small sample size: only 6 cats were involved in the study. A small sample size reduces the significance and undermines the validity of the study because the results are less representative of the entire population and there is a higher margin of error.
• The McCune cat stress score is not a validated scoring system, but it has been regarded as a static and subjective measurement of behaviours displayed over the short term (Broadley et al., 2014). It has extensively been used to evaluate the level of welfare for cats in shelters.
• The 50 mg and 75 mg doses were not randomised.
• The washout period ranged from 4–7 days.
• Subjects were limited to neutered male cats.
• Cats were house in a single room with visual access to the other cats. It is possible that cats were influenced by the stimuli of the other cats’ activities
• One cat did not receive a full dose of the 100 mg trazodone on one treatment day.
• Not all cats received the medication in similar types or amounts of food and some were given additional treats as an incentive which will have altered absorption rates.
• Not all cats entered and exited the carrier voluntarily resulting in different stress levels imposed on each cat.
• It is difficult to apply the finding from this study in clinical practice as the cats are all purpose bred laboratory cats and so likely to behave differently to non-laboratory cats. In addition, it has not been stated that any of the cats had pre-existing signs of veterinary visit related anxiety.

CAB Abstracts on the OVID interface 1973 to 2 April 2024
PubMed accessed via the NCBI website 1920 to 2 April 2024

CAB Abstracts:

1. cat or cats or feline* or queen* or tom or toms
2. trazodone or desyrel or molipaxin or oleptro
3. anxiety or anxious or fear or fearful or stress or stressed or stressful or distressed or distress or panic or phobi* or nervous or nervousness or vocalise* or urinat* or hide or hides
4. 1 and 2 and 3

PubMed:

1. cat or cats or feline or queen or tom or tom
2. trazodone or desyrel or molipaxin or oleptro
3. anxiety or anxious or fear or fearful or stress or stressed or stressful or distressed or distress or panic or phobia or nervous or nervousness or vocalise or urinate or hide or hides
4. 1 and 2 and 3

02 Apr 2024

• Papers inappropriate to the PICO: non-related title or abstract.
• Any other species but cats.
• No direct comparison between use of trazodone and without trazodone/placebo.

• Effects investigated in a veterinary setting.
• Papers in English.
• Cats aged 6 months or older.
• Cats weighing more than 1kg.