Dogs are prescribed a variety of analgesics for treatment of pain, including neuropathic pain. These medications may be used alone or in combination and are often prescribed for several days. Although systemic adverse effects of these medications have been well researched in veterinary medicine, ocular adverse effects have not been well documented. Analgesics that decrease tear production, alter IOP, alter pupil size, expedite TBUT, or decrease corneal sensitivity may predispose dogs to development of ocular abnormalities or worsen existing ocular disease.1 This potential impact is greater in dogs with breed predispositions (eg, brachycephalic breeds) and those with systemic diseases (eg, renal failure, heart failure, endocrinopathies, or gastrointestinal disease).2–9 For instance, medications that impair tear production or destabilize tear film integrity may predispose dogs to developing ulcerative keratitis, medications that increase IOP may worsen existing glaucoma or act as a catalyst for development of glaucoma, and medications that reduce corneal sensitivity may result in a stunted blink reflex, thereby increasing a patient's risk of developing corneal ulceration. Thus, to provide a true overview of effects that a medication may have on ocular health in a patient, a comprehensive ophthalmic evaluation should be considered, including the effects a medication has on tear production, IOP, PD, tear film stability, and corneal sensitivity. This information would enable veterinarians to prevent potentially harmful ocular sequelae and mitigate occurrences of adverse drug reactions.
Unfortunately, there are substantial gaps in the veterinary literature regarding knowledge of the effects of common analgesics on ocular health. Studies3,10–15 have focused on single analgesics or systemically administered sedatives and induction agents, with most focusing on 1 or 2 variables of ocular health and typically lasting for short durations. Commonly prescribed in dogs, gabapentin is a neuropathic pain analgesic and a structural analog of γ-aminobutyric acid, which appears to be most effective in treating chronic pain and neuropathic pain in companion animals.16,17 Tramadol is a synthetic opioid-like μ-receptor agonist with opioid and nonopioid actions that contribute to the drug's analgesic effects in dogs.18,19 Meloxicam is an NSAID with cyclooxygenase-2 preferential inhibition and is commonly prescribed in dogs for its analgesic, anti-inflammatory and antipyretic properties.16 However, despite the common use of these 3 medications in dogs, we were unable to find any comprehensive studies evaluating the effects of oral administration of gabapentin, tramadol, or meloxicam on ocular health in dogs. Given this existing knowledge gap, combined with the potential detrimental and beneficial ocular impact of systemic analgesics in dogs, a more complete analysis of the effects of systemic analgesics on ocular health in dogs is needed. Therefore, the objective of the study reported here was to evaluate the effects of gabapentin, tramadol, and meloxicam on tear production, IOP, PD, TBUT, and CTT in healthy dogs when given orally for 3 days. On the basis of available literature,15,20–22 we hypothesized that gabapentin would decrease IOP and corneal sensitivity but have no effect on tear production, PD, or tear film stability; that tramadol would decrease corneal sensitivity but have no effect on tear production, IOP, PD, or tear film stability; and that meloxicam would have no effect on tear production, IOP, PD, tear film stability, or corneal sensitivity.
Materials and Methods
Approval for the study was obtained from the University of Guelph Animal Care Committee (Animal Utilization Protocol No. 3955). All procedures were performed in accordance with the Canadian Council on Animal Care's guidelines.
Animals
Nine 10-month-old sexually intact male purpose-bred research Beagles were enrolled and housed at the CAF in Guelph, ON, Canada. A sample size of 8 dogs was calculated to determine a difference in the means of the variable IOP23 on the basis of a 2017 study,3 with α = 0.05, β = 0.80, and SD = 3.0 mm Hg and with an expected difference in mean IOP of 2.5 mm Hg. In case a dog had to be dropped from the study (eg, because of illness or injury), an additional dog was added.
Initial examinations
All dogs underwent a general physical examination, including recording of baseline body weight, and had comprehensive blood work, including a CBC and serum biochemical analyses,a conducted by the same investigator (AKS) immediately before the acclimation period. A complete ophthalmic examination was performed by the same investigator (CLP) on both eyes of every dog prior to entry to the study on the first day of the acclimation period. This ophthalmic examination included a neuro-ophthalmic examination (dazzle reflex, menace response, palpebral reflex, and pupillary light reflexes), STT,b rebound tonometry,c fluorescein staining,d slit-lamp biomicroscopy,e and indirect ophthalmoscopy. Then, after administration of 1% tropicamidef (1 drop administered into both eyes once), a fundic examination was performed.
Acclimation period
All dogs underwent a 7-day acclimation period. The duration of acclimation was established on the basis of a previous study22 in which the initial 5 days were deemed necessary to ensure IOPs had returned to baseline. The remaining 2 days of the acclimation period were used to gather data to determine baseline measurements for ocular variables (STT results, IOP, PD, TBUT, and CTT).
During the acclimation period and throughout the study, environmental enrichment was provided to all dogs, and all dogs were fed a commercially available canine kibbleg once daily and had free access to fresh water at all times. Dogs were acclimated to handling, ocular measurement procedures, and administration of wet food at 8 am, 4 pm, and 12 am, the times of which were set to mimic medication administration during the treatment periods. The dogs were exposed to 15 hours of light (ie, 5:30 am to 8:30 pm) and 9 hours of darkness (ie, 8:30 pm to 5:30 am) over a 24-hour period, with a brief period (approx 15 to 20 minutes) of light exposure at midnight to accommodate feeding of wet food at that time. The dogs underwent a daily general physical examination at 2 pm and were walked by CAF handlers immediately after the 4 pm feeding only during the acclimation period and immediately after the 2 pm evaluation during the treatment and washout periods.
Treatment assignments and procedures
A randomized, blinded, case-crossover study with a 6-sequence, 3-treatment, 3-period design was performed. The study design consisted of 3 treatment phases, each with a 3-day treatment period followed by a 7-day washout period. A treatment period of 3 days was chosen because, in our experience, a commonly recommended duration of analgesic treatment following a traumatic or painful event is 3 to 5 days. The lower end of this range was selected to better allow for a crossover study design within the confines of our financial and temporal limitations. Dogs were reweighed the day before starting each treatment period to ensure accurate dosages, and a recheck CBC and serum biochemical analyses were performed on each dog on the last day of both complete washout periods (ie, for treatment phases 1 and 2) to help identify any systemic concerns that may have precluded a dog's participation in a subsequent treatment phase in the sequence.
Block randomization was used by a statistician to randomly assign dogs to 1 of 3 groups for every treatment period, ensuring all treatment phases were balanced with 3 dogs in each treatment group. The dogs were housed in the same room and in the same groups for the duration of the study; however, dogs were separated for all medication administration and watched to ensure their medication was consumed.
The same technician (BLF) administered all medications. Whenever possible, the medication was administered in a meatball of wet foodh in individual, 6-inch-diameter metal dishes that were evaluated afterward to ensure all food and medication had been consumed. If poor subject compliance occurred, medication was syringe fed. Such restricted use of syringe feeding avoided the unnecessary risk of dogs developing aspiration pneumonia or becoming resistant to medication administration.
Treatment assignments were drug A (gabapentin [compoundedi for a resultant formulation of 100 mg/mL], 10 mg/kg, PO, q 8 h24), drug B (tramadol [compoundedi for a resultant formulation of 10 mg/mL], 3 mg/kg, PO, q 8 h24), and drug C (meloxicamj [1.5 mg/mL], 0.2 mg/kg, PO, once on the first day, followed by 0.1 mg/kg, PO, q 24 h for the remaining 2 days).
Drugs A (gabapentin) and B (tramadol) were administered at 8 am, 4 pm, and 12 am to mimic owner administration at home. Drug C (meloxicam) was administered once daily at 8 am to dogs that were also given an equal volume of water added to their wet food at 4 pm and 12 am to ensure the technician remained blinded to the treatment assignments. The primary investigator (AKS) was not present for any treatments and was blinded to all dogs’ treatment assignments for the duration of the study.
Ophthalmic evaluations
All ophthalmic evaluations were performed by the same investigator (AKS), and restraint of the dogs during evaluations was performed by the same technician (BLF), with the exception of a single day during the last washout period when a different restrainer (CAB) was needed. The dogs were always evaluated in the same order, beginning with dog 1 and ending with dog 9. Data collection occurred in the same windowless room in close proximity to the kennel at the CAF. The room's door was closed during every evaluation to limit noise and light contamination. Room temperature and humidity measurementsk were recorded at the start of every ophthalmic evaluation for each dog. Also, in the evaluation room, a light meterl facing the investigator was permanently mounted on the wall at the approximate level of the subjects’ eyes during examinations. Light intensity was recorded at the start of every ophthalmic evaluation, with the investigator seated and facing the subject on the examination table.
For each evaluation, the dog was minimally restrained in a seated position on a raised examination table. The dog's head was held in a natural position,22,25,26 with the technician placing a hand under the mandible and the other hand at the back of the cranium to maintain the head position at a 90° angle to the examination room table. No digital pressure was exerted around the eyes, orbits, or neck, thereby limiting any potential variability in IOP secondary to changes in body position or digital pressure.27,28 All evaluations were conducted on the OS, then on the OD.
All dogs were evaluated 3 times daily (6:30 am, 2 pm, and 7 pm) during the first 5 days of the acclimation period and 4 times daily (6:30 am, 11 am, 2 pm, and 7 pm) during the last 2 days of the acclimation period, during the 3 days of every treatment period, and on the first day of each washout period. On the remaining days of each washout period (days 2 through 7), dogs were evaluated at 6:30 am, 2 pm, and 7 pm. During each evaluation, tear production, IOP, and PD were measured in that order. The STT was used to measure tear production and was performed by inserting the notched end of 1 sterile STT strip into the central region of the ventral conjunctival sac and holding the strip there for 60 seconds. Results were recorded as millimeters per minute.29 Rebound tonometry for measurement of IOP in all dogs was performed with the same tonometerc appropriately calibrated for dogs and with a new probem used for each dog at each evaluation per the manufacturer's recommendation. The tonometer was used according to the manufacturer's instructions, with the probe perpendicular to the central area of the cornea.26,30 The first error-free IOP measurement was considered correct and recorded.30,31 The PD, recorded in millimeters, was measured horizontally with handheld ophthalmic calipers.32,33,n The left PD was measured first, calipers were reset, and then the right PD was measured.
The TBUT was measured only during the 6:30 am evaluations and was performed last of all measurements at that time. The TBUT was performed by moistening a fluorescein strip with a sterile, buffered isotonic ophthalmic solutiono and applying 1 drop of the resulting concentrated fluorescein stain to the OS, blinking the dog's eyelids once, observing the eye with an ophthalmoscope that included a cobalt blue light filter,p and then measuring the duration of time in seconds until dark spots or lines appeared in the fluorescein-stained tear film over the dorsolateral region of the cornea. The measured duration was the TBUT. The procedure was then repeated for the OD, and residual fluorescein stain was flushed° from both eyes.
The CTT was measured only during the 7 pm evaluations on day 5 of the acclimation period, on day 3 of every treatment period, and on day 4 of both complete washout periods. When measured, the CTT was performed last of all measurements. The CTT was evaluated with an esthesiometerq that contained a 0.12-mm nylon filament. A new nylon filament was used for the study, and the esthesiometer was stored per the manufacturer's recommendations for the duration of the study. The CTT was performed with the nylon filament extended to its maximum length of 6 cm and advanced perpendicularly to the surface of the central area of the cornea, until the filament touched the cornea and a slight bend was achieved in the filament. The filament was shortened by 0.5-cm increments until 3 out of 5 touches elicited a blink reflex, defined as the CTT,1,34 which was reported in centimeters. Immediately following the CTT measurement and 12 hours afterward, dogs’ eyes were evaluated for evidence of corneal erosions or ulcers by applying fluorescein stain onto both eyes by gently touching a moistened fluorescein strip to each dorsal bulbar conjunctiva, then evaluating for corneal defects by use of a cobalt blue light filter.p
Evaluation times were selected to ensure changes in IOP and tear production secondary to diurnal rhythm were captured10,22,35 and to measure tear production, IOP, and PD at 3 and 6 hours after the dogs had received their assigned treatments. Schirmer tear test strips, tonometer probes, and fluorescein strips from the same respective production batches and with identical lot numbers were used throughout the duration of the study to prevent possible inconsistencies.35–38
Statistical analysis
All statistical analysis was performed with the same statistical computing software.r Values of P ≤ 0.05 were considered significant.
Descriptive statistics—All continuous variables were checked for normality with a combination of the Shapiro-Wilk test and visual assessment of a histogram before calculation of the summary statistics (means for normally distributed data and medians for nonnormally distributed data). Baseline summary statistics for the variables were calculated from the measurements collected during the last 2 days of the acclimation period. A paired t test or Wilcoxon signed rank test, with a cutoff value of P = 0.05, was used to compare results from the first 5 days with the last 2 days of the acclimation period. Univariable comparisons were made for each ocular variable (STT results, IOP, PD, TBUT, and CTT) by drug (A, B, or C) and dog identification (1 through 9) with the Kruskal-Wallis test (for variables with data not normally distributed) or a 1-way ANOVA (for variables with data normally distributed and confirmed as such with visual evaluation of a box plot).
Linear regression—A linear mixed model was constructed for each ocular variable (STT results, IOP, PD, TBUT, and CTT); therefore, 5 models were created. The dependent variables were the ocular variables measured during the treatment phases. The fixed effects were the summary statistic baseline values for the ocular variables, treatment phase (1, 2, or 3 in the sequence), day (days 1 to 10 for treatment phases 1 and 2; days 1 to 5 for treatment phase 3), time of day (6:30 am, 11 am, 2 pm, or 7 pm evaluation time), eye (OS or OD), drug (A, B, or C), room temperature (°C), humidity (%), and light intensity (luxes). Various random effect and repeated-measures combinations were investigated as well as correlation structures. Each model was constructed with backward elimination. All 2- and 3-way interactions were included in the model, and the model that converged and had the lowest Akaike information criterion was chosen. The residuals were examined for normality and homoscedasticity visually through plotting of residuals and use of normality tests, such as the Shapiro-Wilk test. Logarithmic transformations of the results for a dependent variable were calculated, followed by back transformation, if needed.
Results
All 9 dogs completed the study. One dog had a single episode of vomiting immediately after medication administration (tramadol [drug B]). The medication was not readministered to that dog that day, and the dog's vomiting resolved spontaneously. The models were each run with and without the 1 data point measured after the vomiting episode (the 2 pm measurements for that day), and no change was appreciated in the estimates for the variables or in any of the models; therefore, the 2 pm measurements for the day of the vomiting episode were left in the models. A different dog developed a superficial corneal abrasion (OS) on 2 separate occasions following CTT. Both times, the condition was detected on routine fluorescein staining and was accompanied with no other signs of ocular disease. Healing of the corneal abrasions was documented by serial fluorescein staining at every evaluation time, until the dog's results were negative for fluorescein staining. In both instances, spontaneous resolution of the corneal abrasion was noticed within 11 hours of initial finding. A different dog developed a superficial corneal laceration (OD) following CTT on day 5 of the washout period of treatment assignment phase 1. The corneal laceration was debrided and treated with a topically applied ophthalmic antimicrobials and an ocular lubricantt during the remainder of the washout period only. The dog had results that were negative for fluorescein staining 30 hours after treatment was instituted, and treatment for the corneal laceration was discontinued at that point.
Blood work
All results of baseline CBC and serum biochemical analyses were unremarkable. On the last day of the first washout period, 5 dogs had mildly high counts of band neutrophils (range, 0.31 × 109 to 1.34 × 109 cells/L; reference limit, ≤ 0.3 × 109 cells/L), and 8 dogs had mildly high urea concentrations (range, 9.6 to 13.1 mmol/L; reference range, 3.5 to 9.0 mmol/L). On the last day of the second washout period, results of CBCs were unremarkable; however, 6 dogs had mildly high urea concentrations (range, 9.2 to 11.5 mmol/L). Serum creatinine concentrations were within reference limits at every evaluation, and no abnormal signs were detected in any dog.
Body weight
The median body weight of dogs at the onset of the acclimation period was 10.5 kg (range, 9 to 12.7 kg). During the study, all dogs were reweighed 3 times, and body weights ranged between 9.0 and 13.2 kg over the course of the study. No significant (P = 0.609) change in body weight was detected for any of the dogs during any phase of the study.
Environmental variables
Temperature and humidity in the room used to collect all ocular data ranged from 22°C to 23°C and from 47% to 70% for the duration of the study. In addition, the light intensity in the room used to collect all ocular data ranged between 148 and 190 luxes for the duration of the study.
Ocular variables during the acclimation period
During the acclimation period, measurements of ocular variables included STT results (n = 324 eyes), IOP (324 eyes), PD (324 eyes), TBUT (126 eyes), and CTT (18 eyes), and results of the first 5 days of the acclimation period were compared with those of the last 2 days of the acclimation period (Table 1). However, the CTT was evaluated only once during the acclimation period; thus, a comparison between the first 5 days and the last 2 days could not be performed. Only the mean IOP differed significantly (P = 0.002) between results for days 1 through 5 (14.8 mm Hg) and for days 6 and 7 (14.1 mm Hg) of the acclimation period. The mean measurements from the last 2 days of the acclimation period were designated as baseline measurements for tear production, IOP, and PD and used to determine the summary statistic baseline values, and these values were then used as fixed effects in the linear models. The mean TBUT was 17.6 seconds during the acclimation period, and that value was used as the baseline mean TBUT.
Comparison of repeated ocular measurements of tear production (STT), IOP, PD, TBUT, and CTT in 9 healthy sexually intact male research Beagles during days 1 through 5 versus days 6 and 7 of the acclimation period before entering a randomized, blinded, case-crossover study to determine the effects of each of 3 orally administered analgesics (gabapentin, tramadol, and meloxicam) on measurements of ocular health in dogs.
| Entire acclimation period | Days 1–5 of the acclimation period | Days 6 and 7 of the acclimation period | |||||
|---|---|---|---|---|---|---|---|
| Variable | No. of eyes | Mean (95% CI) | No. of eyes | Mean (95% CI) | No. of eyes | Mean (95% CI) | P value* |
| Tear production (mm/min) | 324 | 21.1 (20.8–21.4) | 180 | 21.2 (20.8–21.5) | 144 | 21.1† (20.6–21.6) | 0.756 |
| IOP (mm Hg) | 324 | 14.5 (14.2–14.8) | 180 | 14.8 (14.4–15.2) | 144 | 14.1† (13.8–14.5) | 0.002 |
| PD (mm) | 324 | 8.8 (8.7–8.8) | 180 | 9.82 (9.6–10.0) | 144 | 9.72† (9.6–9.9) | 0.433 |
| TBUT (s) | 126 | 17.6† (13.4–21.7) | 90 | 17.4 (13.3–21.5) | 36 | 18.0 (13.6–22.4) | 0.433 |
| CTT (cm) | 18 | 3.9† (2.9–4.8) | 18 | 3.9 (2.9–4.8) | 0 | — | — |
Values of P ≤ 0.05 indicated significant difference between results for days 1 to 5 and results for days 6 and 7 of the acclimation period.
Value used as the baseline value for the ocular variable.
— = Not applicable.
Ocular variables during treatment phases
STT—The overall mean STT measurement was 21.0 mm/min (95% CI, 18.2 to 23.9 mm/min; median, 21.0 mm/min; n = 1,566 eyes) for all 9 dogs during the 3 treatment phases and did not differ significantly (P = 0.361) from baseline (21.1 mm/min). In addition, the mean STT measurement did not differ significantly (P = 0.733) for the 9 dogs on the basis of whether they were receiving drug A (gabapentin; 20.9 mm/min; 95% CI, 17.9 to 23.8 mm/min), drug B (tramadol; 21.1 mm/min; 95% CI, 18.1 to 24.1 mm/min), or drug C (meloxicam; 21.1 mm/min; 95% CI, 18.2 to 21.1 mm/min; Figure 1). However, time of day of the evaluations had a significant (P = 0.05) effect on tear production, and the mean STT measurement was significantly (P = 0.05) lower for dogs during the 6:30 am evaluation (20.8 mm/min), compared with the 5 pm evaluation (21.6 mm/min; Figure 2). Results of linear regression with random effects for dog identification, drug, treatment phase, and eye indicated that there were 3 fixed effects and a fixed-effect interaction in the final model that significantly (P ≤ 0.05) affected the STT measurement (Table 2). Although the overall mean STT measurement did not differ significantly from baseline, the model indicated that when the other variables were accounted for, baseline STT measurement impacted the final STT value; however, the resulting difference was not clinically meaningful. Because the interaction between day and time of day, as fixed effects, significantly (P = 0.032) impacted the STT measurement, day was also retained in the model despite not having a significant (P > 0.05) effect by itself. Drug, as a fixed effect, did not have a significant (P = 0.860) effect on the STT measurement.
Aggregated serial mean STT measurements in 9 healthy sexually intact male research Beagles during a randomized, blinded, case-crossover study to determine the effects of each of 3 orally administered analgesics (gabapentin, tramadol, and meloxicam) evaluated in 3 separate and sequential treatment phases, each of which consisted of a 3-day treatment period and a 7-day washout period (represented as left and right, respectively, of the vertical dotted line) following a 7-day acclimation period. The solid lines represent the mean STT measurements over time throughout each treatment phase with drug A (gabapentin [orange]), drug B (tramadol [green]), or drug C (meloxicam [blue]); the shaded areas represent the 95% CIs of the means; and the horizontal dotted line represents the baseline mean STT measurement (21.1 mm/min) from the last 2 days of the acclimation period.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Aggregated serial mean STT measurements in 9 healthy sexually intact male research Beagles during a randomized, blinded, case-crossover study to determine the effects of each of 3 orally administered analgesics (gabapentin, tramadol, and meloxicam) evaluated in 3 separate and sequential treatment phases, each of which consisted of a 3-day treatment period and a 7-day washout period (represented as left and right, respectively, of the vertical dotted line) following a 7-day acclimation period. The solid lines represent the mean STT measurements over time throughout each treatment phase with drug A (gabapentin [orange]), drug B (tramadol [green]), or drug C (meloxicam [blue]); the shaded areas represent the 95% CIs of the means; and the horizontal dotted line represents the baseline mean STT measurement (21.1 mm/min) from the last 2 days of the acclimation period.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Aggregated serial mean STT measurements in 9 healthy sexually intact male research Beagles during a randomized, blinded, case-crossover study to determine the effects of each of 3 orally administered analgesics (gabapentin, tramadol, and meloxicam) evaluated in 3 separate and sequential treatment phases, each of which consisted of a 3-day treatment period and a 7-day washout period (represented as left and right, respectively, of the vertical dotted line) following a 7-day acclimation period. The solid lines represent the mean STT measurements over time throughout each treatment phase with drug A (gabapentin [orange]), drug B (tramadol [green]), or drug C (meloxicam [blue]); the shaded areas represent the 95% CIs of the means; and the horizontal dotted line represents the baseline mean STT measurement (21.1 mm/min) from the last 2 days of the acclimation period.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Box-and-whisker plots of aggregated serial mean STT measurements for the dogs described in Figure 1, with results from the treatment phases grouped on the basis of those from the 6:30 am, 11 am, 2 pm, or 7 pm evaluations. For each plot, the box represents the interquartile (25th to 75th percentile) range, the whiskers represent the range, the solid line in the box represents the median, the asterisk represents the mean, and the solid circles represent outliers. The horizontal dotted line spanning the figure represents the baseline mean STT measurement (21.1 mm/min) from the last 2 days of the acclimation period.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Box-and-whisker plots of aggregated serial mean STT measurements for the dogs described in Figure 1, with results from the treatment phases grouped on the basis of those from the 6:30 am, 11 am, 2 pm, or 7 pm evaluations. For each plot, the box represents the interquartile (25th to 75th percentile) range, the whiskers represent the range, the solid line in the box represents the median, the asterisk represents the mean, and the solid circles represent outliers. The horizontal dotted line spanning the figure represents the baseline mean STT measurement (21.1 mm/min) from the last 2 days of the acclimation period.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Box-and-whisker plots of aggregated serial mean STT measurements for the dogs described in Figure 1, with results from the treatment phases grouped on the basis of those from the 6:30 am, 11 am, 2 pm, or 7 pm evaluations. For each plot, the box represents the interquartile (25th to 75th percentile) range, the whiskers represent the range, the solid line in the box represents the median, the asterisk represents the mean, and the solid circles represent outliers. The horizontal dotted line spanning the figure represents the baseline mean STT measurement (21.1 mm/min) from the last 2 days of the acclimation period.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Final mixed-effects linear regression model for STT measurements in the dogs described in Table 1 with fixed effects for drug (A [gabapentin], B [tramadol], or C [meloxicam]), day (days 1 to 10 for treatment phases 1 and 2; days 1 to 5 for treatment phase 3), time of day (6:30 am, 11 am, 2 pm, or 7 pm evaluations), and baseline mean STT result.
| Fixed effect | P value |
|---|---|
| Drug | 0.860 |
| Day | 0.110 |
| Time of day | 0.002 |
| Baseline STT | 0.047 |
| Baseline STT2 | 0.039 |
| Day × time of day | 0.032 |
IOP—The overall mean IOP was 14.0 mm Hg (95% CI, 13.9 to 14.1 mm Hg; median, 14.0 mm Hg; n = 1,566 eyes) for all dogs during the 3 treatment phases. The mean IOP was significantly (P = 0.019) lower for dogs during the treatment phases for drug A (gabapentin; 13.8 mm Hg; 95% CI, 11.6 to 16.1 mm Hg) and drug B (tramadol; 13.8 mm Hg; 95% CI, 11.6 to 16.0 mm Hg), compared with drug C (meloxicam; 14.1 mm Hg; 95% CI, 11.8 to 14.1 mm Hg; Figure 3). Time of day when evaluations were performed also significantly (P < 0.001) affected IOP, with the mean IOP significantly (P < 0.001) higher in dogs during the 6:30 am evaluations (14.7 mm Hg), compared with the 11 am (13.5 mm Hg), 2 pm (13.7 mm Hg), and 7 pm (13.7 mm Hg) evaluations (Figure 4). When results were considered by day of the treatment phase, the peak mean IOP (14.3 mm Hg) occurred on day 4 and was significantly (P < 0.041) higher than the value on all other days, except days 1 (14.0 mm Hg) and 2 (14.0 mm Hg). The mean IOP was also significantly (P < 0.006) higher for dogs in treatment phase 3 (14.0 mm Hg), compared with earlier phases 1 (13.9 mm Hg) and 2 (13.9 mm Hg). Results of linear regression and repeated measures with a correlation structure indicated 6 significant (P ≤ 0.05) fixed effects in the final model for IOP and 2 interactions (Table 3). When fixed effects of treatment phase, day, time of day, dog identification, baseline mean IOP, and eye were accounted for in the model, the variable for drug significantly (P = 0.038) affected IOP, with a lower mean IOP in dogs when receiving drugs A (gabapentin; 13.8 mm Hg) or B (tramadol; 13.8 mm Hg), compared with results for drug C (meloxicam; 14.1 mm Hg) or at baseline (14.1 mm Hg). The fixed-effect interactions of baseline mean IOP with drug and baseline mean IOP with time of day indicated that the effect of drug and time of day varied by the dog's baseline mean IOP such that dogs with lower baseline mean IOPs were less affected by drug C and time of day than were dogs with higher baseline mean IOPs. Furthermore, the mean IOP was significantly (P < 0.001) lower in OSs (evaluated first; 13.6 mm Hg), compared with ODs (evaluated second; 14.2 mm Hg).
Aggregated serial mean IOP in the dogs described in Figure 1. The solid lines represent the mean IOP over time throughout each treatment phase with drug A (gabapentin [orange]), drug B (tramadol [green]), or drug C (meloxicam [blue]), and the horizontal dotted line represents the baseline mean IOP (14.5 mm Hg). See Figure 1 for the remainder of the key.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Aggregated serial mean IOP in the dogs described in Figure 1. The solid lines represent the mean IOP over time throughout each treatment phase with drug A (gabapentin [orange]), drug B (tramadol [green]), or drug C (meloxicam [blue]), and the horizontal dotted line represents the baseline mean IOP (14.5 mm Hg). See Figure 1 for the remainder of the key.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Aggregated serial mean IOP in the dogs described in Figure 1. The solid lines represent the mean IOP over time throughout each treatment phase with drug A (gabapentin [orange]), drug B (tramadol [green]), or drug C (meloxicam [blue]), and the horizontal dotted line represents the baseline mean IOP (14.5 mm Hg). See Figure 1 for the remainder of the key.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Box-and-whisker plots of aggregated serial mean IOP measurements for the dogs described in Figure 1, with results from the treatment phases grouped on the basis of those from the 6:30 am, 11 am, 2 pm, or 7 pm evaluations. The horizontal dotted line spanning the figure represents the baseline mean IOP measurement (14.5 mm Hg). See Figure 2 for the remainder of the key.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Box-and-whisker plots of aggregated serial mean IOP measurements for the dogs described in Figure 1, with results from the treatment phases grouped on the basis of those from the 6:30 am, 11 am, 2 pm, or 7 pm evaluations. The horizontal dotted line spanning the figure represents the baseline mean IOP measurement (14.5 mm Hg). See Figure 2 for the remainder of the key.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Box-and-whisker plots of aggregated serial mean IOP measurements for the dogs described in Figure 1, with results from the treatment phases grouped on the basis of those from the 6:30 am, 11 am, 2 pm, or 7 pm evaluations. The horizontal dotted line spanning the figure represents the baseline mean IOP measurement (14.5 mm Hg). See Figure 2 for the remainder of the key.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Final mixed-effects linear regression model for IOP in the dogs described in Table 1.
| Fixed effect | P value |
|---|---|
| Drug | 0.038 |
| Phase | 0.001 |
| Eye | < 0.001 |
| Day | < 0.001 |
| Time of day | < 0.001 |
| Baseline mean IOP | < 0.001 |
| Baseline mean IOP × time of day | < 0.001 |
| Baseline mean IOP × drug | 0.005 |
PD—The mean PD was 8.8 mm (95% CI, 8.7 to 8.8 mm; median, 9.0 mm; n = 1,566 eyes) for all dogs during the 3 treatment phases. The mean PD did not differ significantly (P = 0.270) on the basis of whether dogs were receiving drug A (gabapentin; 8.6 mm; 95% CI, 7.8 to 9.4 mm), drug B (tramadol; 8.6 mm; 95% CI, 7.8 to 9.3 mm), or drug C (meloxicam; 8.5 mm; 95% CI, 7.8 to 9.2 mm; Figure 5). However, time of day when evaluations were performed significantly (P < 0.001) affected PD, and the mean PD was significantly (P < 0.001) smaller for dogs during the 6:30 am evaluations (8.32 mm), compared with the 11 am (8.54 mm), 2 pm (8.71 mm), and 7 pm (8.69 mm) evaluations (Figure 6). A mixed-effects linear regression model, with random effects for drug, day, dog identification, and treatment phase, was constructed, and there were 6 fixed effects and a fixed-effect interaction that significantly (P ≤ 0.05) affected PD (Table 4). Drug, as a fixed effect, did not significantly (P = 0.188) impact PD; however, the mean PD was significantly (P = 0.022) larger at baseline (9.8 mm), compared with the overall mean PD throughout the 3 treatment phases (8.8 mm). Eye, as a fixed effect, had a P value of exactly 1.0, which indicated no difference in mean PD for OSs versus ODs.
Aggregated serial mean PD in the dogs described in Figure 1. The solid lines represent the mean PD over time throughout each treatment phase with drug A (gabapentin [orange]), drug B (tramadol [green]), or drug C (meloxicam [blue]), and the horizontal dotted line represents the baseline mean PD (9.72 mm). See Figure 1 for the remainder of the key.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Aggregated serial mean PD in the dogs described in Figure 1. The solid lines represent the mean PD over time throughout each treatment phase with drug A (gabapentin [orange]), drug B (tramadol [green]), or drug C (meloxicam [blue]), and the horizontal dotted line represents the baseline mean PD (9.72 mm). See Figure 1 for the remainder of the key.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Aggregated serial mean PD in the dogs described in Figure 1. The solid lines represent the mean PD over time throughout each treatment phase with drug A (gabapentin [orange]), drug B (tramadol [green]), or drug C (meloxicam [blue]), and the horizontal dotted line represents the baseline mean PD (9.72 mm). See Figure 1 for the remainder of the key.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Box-and-whisker plots of aggregated serial mean PD measurements for the dogs described in Figure 1, with results from the treatment phases grouped on the basis of those from the 6:30 am, 11 am, 2 pm, or 7 pm evaluations. The horizontal dotted line spanning the figure represents the baseline mean PD measurement (9.72 mm). See Figure 2 for the remainder of the key.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Box-and-whisker plots of aggregated serial mean PD measurements for the dogs described in Figure 1, with results from the treatment phases grouped on the basis of those from the 6:30 am, 11 am, 2 pm, or 7 pm evaluations. The horizontal dotted line spanning the figure represents the baseline mean PD measurement (9.72 mm). See Figure 2 for the remainder of the key.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Box-and-whisker plots of aggregated serial mean PD measurements for the dogs described in Figure 1, with results from the treatment phases grouped on the basis of those from the 6:30 am, 11 am, 2 pm, or 7 pm evaluations. The horizontal dotted line spanning the figure represents the baseline mean PD measurement (9.72 mm). See Figure 2 for the remainder of the key.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Final mixed-effects linear regression model for PD in the dogs described in Table 1.
| Fixed effect | P value |
|---|---|
| Drug | 0.188 |
| Day | < 0.001 |
| Time of day | 0.001 |
| Baseline mean PD | 0.022 |
| Baseline mean PD2 | 0.021 |
| Light | < 0.001 |
| Light2 | < 0.001 |
| Light × time of day | < 0.001 |
TBUT—The mean TBUT was 17.4 seconds (95% CI, 13.7 to 21.2 seconds; median, 17.3 seconds; n = 450 eyes) for all dogs during the 3 treatment phases. The mean TBUT did not differ significantly (P = 0.572) for dogs on the basis of whether they were receiving drug A (gabapentin; 17.2 seconds; 95% CI, 13.4 to 20.9 seconds), drug B (tramadol; 17.6 seconds; 95% CI, 14.0 to 21.2 seconds), or drug C (meloxicam; 17.5 seconds; 95% CI, 13.8 to 21.1 seconds; Figure 7). However, the mean TBUT was significantly higher for dogs during phase 3 (18.6 seconds), compared with phase 1 (16.9 seconds; P < 0.001) or 2 (17.3 seconds; P = 0.012). With each subsequent phase in the sequence, the mean TBUT increased (0.366 seconds for phase 1 vs 2, 1.337 seconds for phase 2 vs 3, and 1.704 seconds for phase 1 vs 3). Results of a linear regression model that accounted for random effects of treatment phase, dog identification, and drug indicated that the only significant fixed effects in the model were treatment phase (P = 0.048) and day (P = 0.003). Drug did not have a significant (P = 0.729) effect on the TBUT. Notably, the models for TBUT and CTT were the only ones in which baseline as a fixed effect was not significant in the model.
Aggregated serial mean TBUT results in the dogs described in Figure 1. The solid lines represent the mean TBUT over time throughout each treatment phase with drug A (gabapentin [orange]), drug B (tramadol [green]), or drug C (meloxicam [blue]), and the horizontal dotted line represents the baseline mean TBUT (17.6 seconds). See Figure 1 for the remainder of the key.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Aggregated serial mean TBUT results in the dogs described in Figure 1. The solid lines represent the mean TBUT over time throughout each treatment phase with drug A (gabapentin [orange]), drug B (tramadol [green]), or drug C (meloxicam [blue]), and the horizontal dotted line represents the baseline mean TBUT (17.6 seconds). See Figure 1 for the remainder of the key.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Aggregated serial mean TBUT results in the dogs described in Figure 1. The solid lines represent the mean TBUT over time throughout each treatment phase with drug A (gabapentin [orange]), drug B (tramadol [green]), or drug C (meloxicam [blue]), and the horizontal dotted line represents the baseline mean TBUT (17.6 seconds). See Figure 1 for the remainder of the key.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
CTT—The mean CTT was 2.8 cm (95% CI, 1.6 to 3.9 cm; median, 2.5 cm; n = 90 eyes) for the 9 dogs during the 3 treatment phases. The mean CCT did not differ significantly (P = 0.625) for dogs on the basis of whether they were receiving drug A (gabapentin; 2.6 cm; 95% CI, 1.6 to 3.6 cm), B (tramadol; 2.6 cm; 95% CI, 1.5 to 3.8 cm), or C (meloxicam; 2.4 cm; 95% CI, 1.5 to 3.3 cm). Results of a linear regression model that accounted for random effects in drug, treatment phase, dog identification, and day indicated that day was the only significant (P < 0.001) fixed effect in the final model for CTT. The mean CTT was 0.3 cm shorter on day 3 of the treatment period (2.2 cm) than on day 4 of the washout period (2.5 cm). Neither drug nor baseline mean CTT significantly (P = 0.320 and P = 0.057, respectively) affected mean CTT during the treatment phases (Figure 8).
Aggregated serial mean CTT results in the dogs described in Figure 1. The solid lines represent the mean CTT over time throughout each treatment phase with drug A (gabapentin [orange]), drug B (tramadol [green]), or drug C (meloxicam [blue]), and the horizontal dotted line represents the baseline mean CTT (3.9 cm). See Figure 1 for the remainder of the key.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Aggregated serial mean CTT results in the dogs described in Figure 1. The solid lines represent the mean CTT over time throughout each treatment phase with drug A (gabapentin [orange]), drug B (tramadol [green]), or drug C (meloxicam [blue]), and the horizontal dotted line represents the baseline mean CTT (3.9 cm). See Figure 1 for the remainder of the key.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
Aggregated serial mean CTT results in the dogs described in Figure 1. The solid lines represent the mean CTT over time throughout each treatment phase with drug A (gabapentin [orange]), drug B (tramadol [green]), or drug C (meloxicam [blue]), and the horizontal dotted line represents the baseline mean CTT (3.9 cm). See Figure 1 for the remainder of the key.
Citation: American Journal of Veterinary Research 81, 12; 10.2460/ajvr.81.12.973
All of the final models converged and had homoscedasticity of the residuals; therefore, we are confident in their structure and results. In addition, some important nonassociations were the lack of effect that carryover had on the models (all P > 0.05) and lack of effect by the environmental variables (room temperature, humidity, and light) on all ocular measurements, except for the significant (P < 0.001) effect of light on PD.
Discussion
The objective of the present study was to evaluate the effects of orally administered gabapentin, tramadol, and meloxicam, individually, on tear production, IOP, PD, TBUT, and CTT in healthy dogs when given for 3 days. The study protocol was designed to capture a large volume of information regarding the drugs’ effects on the 5 ocular variables selected because of their clinical relevance in ocular health in dogs. To our knowledge, the present study was one of the most comprehensive ocular studies conducted on dogs. Our resulting data set allowed for extensive statistical analysis, and the breadth and scope of our data ultimately enabled us to examine not only for impacts that the drugs may have had on the ocular variables of interest, but also for biological interactions and effects on these variables that other studies have been unable to address. Another unique feature of our study was secondary to the complex mixed linear regression models that we created, allowing us to account for the dependency of repeated measures within each of the dogs, at multiple times throughout the day and on different days, and for separate treatment phases. Not accounting for this dependency would have violated the assumptions of independence for many routine statistical tests.
The acclimation period was evaluated as 2 separate periods on the basis of results from a study22 that shows IOP values in dogs took 5 days to return to baseline levels. Clearly, an appropriately long acclimation period is necessary to help ensure collected data are as representative of a patient's true clinical state as possible, and potential reasons for changes in measurements of ocular variables could include a dog's stress level at the time of testing, handler abilities, operator technique, and challenges associated with instrumentation.27,30,39–41 Although results for the STT, PD, TBUT, and CTT did not differ between the first 5 days and last 2 days of the acclimation period in the present study, our findings indicated that IOP differed significantly and supported the conclusion that a minimum of 5 days is required for IOP values to return to baseline in healthy dogs.22 Similarly, our findings supported that a 7-day washout period adequately ensured the preceding drug had no appreciable impact on the ocular variables measured in subsequent phases in the sequences of the present study.
Our results indicated that tear production did not differ on the basis of drug treatment and that although the model indicated that when the other variables were accounted for, baseline STT measurement impacted the final STT value, the resulting difference was not clinically meaningful. A statistically significant effect was also detected for time of day, which was mainly driven by higher mean STT results for evaluations performed at later times as the day progressed. These results were consistent with previous studies35,42 that show a nocturnal peak in tear production.
Results of the present study indicated that only gabapentin and tramadol affected mean IOP, with a resultant decrease of 0.45 and 0.35 mm Hg, respectively, from baseline mean IOP. This decrease was not considered clinically meaningful in healthy dogs; however, this effect should be further evaluated in animals with clinical disease associated with glaucoma. The difference in the mean IOP between OSs (13.6 mm Hg) and ODs (14.2 mm Hg) was unexpected but could have been explained by the lack of randomization between eyes because the OS was always examined first in the present study. This finding also serves as a reminder to randomize all aspects of clinical trials, including eyes. In addition, the mean IOP was highest at 6:30 am evaluations and appeared to decrease as the day progressed. This finding was consistent with previous reports22,35 that IOP has a diurnal acrophase. Although previous studies show that a single oral dose of gabapentin appears to prevent an increase in IOP following induction of general anesthesia20 and that tramadol administered IM at doses of 4 and 6 mg/kg has no effect on tear production, IOP, or PD in healthy dogs,21 neither investigation allowed for intersubject comparisons because no crossover design was used and because IOP was evaluated for only 15 minutes following drug administration.
Pupillary diameter was significantly higher during the acclimation period than at any other time during the present study. This finding was consistent with an anticipated increase in subject stress and subsequent sympathetic tone during the acclimation period, resulting in mydriasis.1,43 This finding also suggested that PD should be evaluated following an appropriate acclimation period to ensure accuracy of results and that our acclimation period of 7 days may not have been long enough to attain true baseline levels. Another interesting finding was that there was no difference in PD for OSs versus ODs. A variation between eyes was anticipated, given how prone PD is to change secondary to environmental and physiologic effects and that all evaluations were performed on the OS, followed by the OD. However, a lack of variation was also expected on the basis of the method by which measurements were obtained.44 Because of the interaction terms in the present study, it was a challenge to identify that light had a significant impact on PD. After a closer look at the data, we identified large variability in the light intensity measured at 10 am versus 7 pm (range, 148 to 190 luxes), which was likely the reason that PD was impacted. Because all PD measurements on all subjects were obtained in the same windowless room located inside another windowless room with no external light contamination, the reason for variability in light levels may have been fluctuations in the CAF's actual lighting system, bulbs, or both.
During the treatment phases, there were fewer measurements of TBUT (n = 450 eyes) and CTT (90 eyes), compared with measurements of tear production, IOP, and PD (1,566 eyes each). With fewer data points for TBUT and CTT, it was more challenging to detect changes in those variables. Treatment phase impacted TBUT in that with each subsequent phase in the sequence, the mean TBUT increased. The reason for this increase is unknown; however, it could have been secondary to an increase in operator proficiency when performing this subjective test. With respect to CTT, it appeared that the dogs in the present study were more tolerant of corneal touching with a 0.3-cm-longer length of filament on day 4 of the washout period, compared with a shorter length on day 3 of the treatment period. This finding was unrelated to treatment phase and was thus challenging to simply attribute to a learned tolerance of the procedure. During our study, a wide range in humidity was identified, and the type of filament used for CTT is known to absorb water over time,45 resulting in a less rigid filament and a longer CTT. However, an impact by humidity on CTT was not detected during our regression analysis. Nonetheless, it was possible that we were unable to detect such a potential impact owing to fewer data points for CTT.
Few adverse effects were detected during the present study. The first adverse effect was related to CTT and resulted in iatrogenic corneal trauma. The second adverse event was related to a single episode of vomiting in 1 dog following administration of tramadol. This episode of vomiting may have been secondary to syringe feeding of the medication or stress associated with handling. Because there was no impact on any of the models after the removal of the measurements obtained from the affected dog's next ocular evaluation, it was thought that this vomiting episode had little impact on the results.
Anomalies noticed on blood work could have been considered adverse events; however, at no time did any dog in the present study display clinical signs secondary to the abnormalities noticed. Abnormalities on CBCs were attributed to delays in sample preparation46 and were considered spurious following blood smear evaluation by a veterinary clinical pathologist.u The mildly high BUN concentrations could have been attributable to a delay in sample separation, hemolysis of the sample, or a sample drawn after food had not been withheld46 and were not considered clinically meaningful because no dog showed any signs of systemic disease and because serum creatinine concentrations were all within reference limits.u Additional testing, including a urinalysis, to rule out renal causes of high urea concentration could have been pursued; however, this was not considered necessary because creatinine values were always within reference limits. Furthermore, additional testing (eg, fecal analysis with evaluation for occult blood) to rule out underlying gastrointestinal disease as a cause of the high urea concentration was not pursued because no dog had signs of systemic disease and none of the affected dogs were concurrently receiving meloxicam.
Limitations of the present study included a lack of diversity in the available study population, and results may not have been representative of the effect of these medications in the general dog population. The use of liquid-compounded gabapentin and tramadol was determined necessary to ensure that the doses administered to each dog were as accurate as possible. These medications were compounded by a veterinary pharmacy with strict quality control practices and verified compounding practices47,48; however, inaccuracies in the quoted concentration of medications administered were possible. For future studies in which compounded medications are to be used, investigators may consider verifying quoted doses of the medications. The same dosages were used for gabapentin (10 mg/kg, PO q 8 h) and tramadol (3 mg/kg, PO, q 8 h) throughout the present study; it was possible that at higher dosages, statistically and clinically significant effects on the ocular variables evaluated could have been appreciated. In the future, comparisons of different dosage ranges for the evaluated medications may be informative. In the present study, the OS was always evaluated first. In contrast to other studies22,35 that did not find a meaningful difference between eyes, our results indicated that eye, as a fixed effect, had substantial impacts on tear production and IOP, and we advise investigators to randomize which eye is evaluated first in future studies. Another potential limitation was that we elected to use the first error-free reading in IOP measurements because this practice has been used in previous studies30,31 and clinical practice; however, we acknowledge that other studies22,25 have obtained 3 error-free readings and then used the resulting mean for statistical analysis. Lastly, although there was a single day when a different restrainer (CAB) was used, this change was not noticed to have any effect on the data collected.
Results of our study indicated that gabapentin, tramadol, and meloxicam, when given orally at the quoted doses for 3 consecutive days, should have no clinically adverse effects on tear production, IOP, PD, tear film stability, or corneal sensitivity in healthy dogs. In addition, our results did not indicate a decrease in corneal sensitivity during treatment, suggesting that these analgesics do not provide a clinically meaningful analgesic effect on the cornea.
In the present study, we sought to address the existing knowledge gap of the effect that oral analgesics have on variables of ocular health in dogs. Future studies could include evaluation of various dosage ranges of commonly prescribed oral analgesics, their effects on a more representative study population, and their effects in patients with preexisting ocular diseases.
Acknowledgments
This manuscript represents part of a thesis submitted by Dr. Shukla to the Ontario Veterinary College Department of Clinical Studies as partial fulfillment of the requirements for a Master of Science degree.
Funded by the Pet Trust at the Ontario Veterinary College.
The authors declare that there were no conflicts of interest.
Presented in abstract form at the 50th Annual American College of Veterinary Ophthalmologists Meeting, Maui, Hawaii, November 2019.
The authors thank William Sears for his assistance with statistical analysis.
ABBREVIATIONS
| CAF | Central Animal Facility |
| CTT | Corneal touch threshold |
| IOP | Intraocular pressure |
| OD | Right eye |
| OS | Left eye |
| PD | Pupillary diameter |
| STT | Schirmer tear test |
| TBUT | Tear break-up time |
Footnotes
Animal Health Laboratory, Laboratory Services Division, University of Guelph, ON, Guelph Canada.
Eagle Vision, Katena Products Inc, Denville, NJ.
TonoVet Type TVO1, Tiolat Oy, Finland.
Fluorescein sodium, Optitech Eyecare, Med Devices Life-sciences Ltd, London, England.
SL-15 portable slitlamp, Kowa, Tokyo, Japan.
Mydriacyl 1%, Alcon Canada Inc, Mississauga, ON, Canada.
Pro Plan Savor Adult Chicken and Rice Formula, Nestlé Purina PetCare Co, St Louis, Mo.
Gastrointestinal High Energy Canine, Royal Canin, Aimargues, Gard, France.
Ontario Veterinary College Pharmacy, University of Guelph, Guelph, ON, Canada.
Metacam, Boehringer-Ingelheim, Burlington, ON, Canada.
AcuRite indoor thermometer and humidity monitor, Chaney Instrument Co, Lake Geneva, Wis.
Fisherbrand Traceable Dual-Range Light Meter, Fisher Scientific, Ottawa, ON, Canada.
TonoVet probe, ICare Finland Oy, Vantaa, Finland.
Storz Jameson Caliper E-2410, Bausch & Lomb Inc, Heidelberg, Germany.
Sensitive Eyes Saline Plus, Bausch & Lomb Inc, Rochester, NY.
Ophthalmoscope, Welch Allyn Inc, Skaneateles Falls, NY.
Cochet-Bonnet esthesiometer, Luneau Ophthalmologie, Chartres, France.
R: A language and environment for statistical computing, version 5.3.1/R and Studio version 1.1.456, R Foundation for Statistical Computing, Vienna, Austria.
Tobramycin 0.3%, Sandoz Canada, Mississauga, ON, Canada.
Tear-Gel, Bausch & Lomb Inc, Rochester, NY.
Ruotsalo K, Clinical Pathologist and Adjunct Faculty, Animal Health Laboratory, University of Guelph, Guelph, ON, Canada: Personal communication, 2018.
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