Evaluation of the perioperative analgesic effects of grapiprant compared with carprofen in dogs undergoing elective ovariohysterectomy

Juliet M. Ross Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN

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Stephanie A. Kleine Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN

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Christopher K. Smith Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN

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Rebekah K. DeBolt Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN

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Jennifer Weisent Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN

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Emma Hendrix Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN

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Reza Seddighi Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN

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Abstract

OBJECTIVE

To evaluate and compare postoperative analgesic effects of grapiprant and carprofen in dogs undergoing ovariohysterectomy.

ANIMALS

42 sexually intact female healthy dogs (< 35 kg and 0.5 to 7 years old) were enrolled.

PROCEDURES

In a masked, randomized, noninferiority clinical trial, dogs received either 2 mg/kg of grapiprant or 4.4 mg/kg of carprofen orally 2 hours prior to ovariohysterectomy. Postoperative pain was assessed using the Glasgow Composite Pain Scale–Short Form (GCPS-SF) at extubation and 2, 4, 6, 8, 18, and 24 hours postextubation and compared to baseline. After each pain scoring, mechanical nociceptive testing with von Frey monofilaments (vF) was performed to assess hyperalgesia. Hydromorphone (0.05 mg/kg, IM) was administered to any dog with a GCPS-SF of ≥ 5/24. The noninferiority limit (NI) for the GCPS-SF was Δ = 3. The NI for vF was Δ = –0.2. Following noninferiority, a mixed-effect ANOVA and post hoc comparisons were made with the Tukey correction method (P < .05).

RESULTS

3 dogs required rescue analgesia and were excluded from statistical analysis. Of the remaining 39 dogs, the upper CI for GCPS-SF was below the NI of 3 and the lower CI for vF was greater than the NI of –0.2, indicating noninferiority of grapiprant as compared to carprofen. There was no difference between treatment (P = .89) nor treatment by time (P = .62) for GCPS-SF. There was no difference between groups at any time point or over time when vF were used.

CLINICAL RELEVANCE

Our study results support the use of grapiprant as an analgesic alternative to carprofen in dogs undergoing ovariohysterectomy.

Abstract

OBJECTIVE

To evaluate and compare postoperative analgesic effects of grapiprant and carprofen in dogs undergoing ovariohysterectomy.

ANIMALS

42 sexually intact female healthy dogs (< 35 kg and 0.5 to 7 years old) were enrolled.

PROCEDURES

In a masked, randomized, noninferiority clinical trial, dogs received either 2 mg/kg of grapiprant or 4.4 mg/kg of carprofen orally 2 hours prior to ovariohysterectomy. Postoperative pain was assessed using the Glasgow Composite Pain Scale–Short Form (GCPS-SF) at extubation and 2, 4, 6, 8, 18, and 24 hours postextubation and compared to baseline. After each pain scoring, mechanical nociceptive testing with von Frey monofilaments (vF) was performed to assess hyperalgesia. Hydromorphone (0.05 mg/kg, IM) was administered to any dog with a GCPS-SF of ≥ 5/24. The noninferiority limit (NI) for the GCPS-SF was Δ = 3. The NI for vF was Δ = –0.2. Following noninferiority, a mixed-effect ANOVA and post hoc comparisons were made with the Tukey correction method (P < .05).

RESULTS

3 dogs required rescue analgesia and were excluded from statistical analysis. Of the remaining 39 dogs, the upper CI for GCPS-SF was below the NI of 3 and the lower CI for vF was greater than the NI of –0.2, indicating noninferiority of grapiprant as compared to carprofen. There was no difference between treatment (P = .89) nor treatment by time (P = .62) for GCPS-SF. There was no difference between groups at any time point or over time when vF were used.

CLINICAL RELEVANCE

Our study results support the use of grapiprant as an analgesic alternative to carprofen in dogs undergoing ovariohysterectomy.

Introduction

Nonsteroidal anti-inflammatory drugs are common analgesic agents used perioperatively.1,2 Most traditional NSAIDs are easily administered at home to dogs during the pre- and postoperative period. They are available as oral and parenteral formulations providing a component of an effective, long-lasting analgesic protocol.3 For instance, carprofen provides effective perioperative analgesia in dogs undergoing ovariohysterectomy for up to 24 hours.25 In this population, there is evidence that NSAIDs are more effective when administered preoperatively.2 Despite this evidence, NSAIDs are often administered in the postoperative period in an attempt to reduce NSAID-associated adverse effects, particularly renal injury. Purportedly, the renal adverse effects are potentiated by anesthesia-induced hypotension and reduced tissue perfusion.1 Despite the lack of significant evidence for NSAID-induced adverse effects,6 the misperception regarding the commonality of these effects has led to a search for drugs that can potentially provide a more desirable safety profile while providing similar analgesic benefits.7

Nonselective inhibition of all prostaglandin production through blockade of cyclooxygenase (COX) is the primary mechanism responsible for the analgesic effects of traditional NSAIDs. Unfortunately, this mechanism is also responsible for the adverse gastrointestinal, renal, and thrombotic effects.3 Prostaglandin E2 (PGE2) is the principal proinflammatory prostanoid produced via the COX pathway and is expressed in numerous tissues throughout the body. Physiologic and pathological effects of PGE2 are mediated through binding 4 G-protein–coupled receptors (EP1-4).8 Effects of PGE2 vary depending on the tissue distribution and intracellular signaling pathways of each individual receptor. Previous studies have demonstrated that the EP4 receptor is the principal mediator of PGE2’s role in inflammation.9 However, the effect of preemptive, selective blockade of the EP4 receptor on postoperative acute inflammatory pain in dogs is unknown.

Grapiprant is an EP4 receptor antagonist approved in the US for treatment of chronic, inflammatory pain associated with osteoarthritis in dogs.10 This medication belongs to the piprant class of drugs and is considered a novel NSAID due to its unique, highly selective mechanism of action. Through sole binding to the EP4 receptor, piprants allow for the COX-derived prostaglandins to be both produced and active at receptors other than EP4. Currently, grapiprant is the only commercially available piprant NSAID. It binds competitively to a single site and shows high affinity for the EP4 receptor.11 The established oral dose of grapiprant in dogs is 2 mg/kg every 24 hours10; however, it has been shown that this medication is very safe with minimal adverse effects at doses up to 50 mg/kg.12

To date, there are no data evaluating the efficacy of grapiprant for acute postoperative pain. The current study was conducted to evaluate postoperative analgesic effects of grapiprant compared to carprofen in controlling acute postoperative soft tissue pain in dogs undergoing ovariohysterectomy. The Glasgow Composite Pain Scale–Short Form (GCPS-SF)13 was used to assess pain, and mechanical nociceptive testing (MNT) was used to assess mechanical wound sensitivity and hyperalgesia. Our null hypothesis was that, in dogs undergoing ovariohysterectomy, grapiprant would be less efficacious than carprofen in producing postoperative analgesia.

Materials and Methods

Animals

A total of 42 healthy, sexually intact female dogs from local animal shelters, aged between 6 months and 7 years and weighing between 5 and 35 kg, were enrolled in the study. Up to 5 dogs from a single shelter were evaluated at a time to reduce the risk of accidental spread of parasitic or viral infections among shelters.

After arrival at the research facility, the general health of dogs was confirmed by performing a complete physical examination and basic laboratory testing including PCV, total solids, and blood glucose concentration. For each animal, hair was clipped over the ventral abdomen for visualization of possible midline surgical scars or tattoos indicative of previous ovariohysterectomy. A small area of fur was also clipped over the dorsal flank just cranial to the wing of the ilium for MNT testing. After physical examination, values for GCPS-SF and MNT were determined. Dogs that were already receiving NSAIDs or corticosteroids, were already ovariohysterectomized, displayed any clinical signs of systemic disease, or displayed aggressive behavior in response to manipulation were excluded.

Following enrollment, all dogs were acclimated to the research facility for a minimum of 12 hours. Dogs were housed in individual runs and always had access to fresh water. The housing facility was temperature and humidity controlled in accordance with IACUC standards.

Experimental design

This study was a masked, randomized clinical trial approved by the University of Tennessee IACUC (protocol No. 2829-0321) and in accordance with all Animal Research: Reporting of In Vivo Experiments guidelines.13 A priori sample size calculation revealed that a total of at least 34 dogs (17 dogs/treatment group) were needed to detect noninferiority with an α = 0.05 and β < 0.2 using a 1-sided, 2-sample t test with unequal variances. The calculation was based on 2 prospective studies; one included evaluation of GCPS-SF and MNT scores, and the second study included GCPS-SF evaluation.2,14 The MNT margin of noninferiority was –0.2 with a mean of 6.59 and SD (SD) of 1.5.

Dogs were randomly assigned to 1 of 2 treatment groups: CAR received 4.4 mg/kg of carprofen PO and GRAP received 2 mg/kg of grapiprant PO. Treatments for both groups were administered 2 hours prior to anesthesia. Dogs were randomized using a 2-factor stratification in a split-split plot design (JMP version 16; SAS Institute Inc). The factors of randomization included surgeon and body weight. This ensured treatments were evenly distributed between surgeons (RD and JW) and dogs weighing ≤ 10 kg compared to those weighing > 10 kg. To maintain masking throughout the study, 1 individual aware of treatment allocation was responsible for administering study drugs to all dogs.

Anesthesia and surgical procedure

Animals were fasted for approximately 12 hours before induction of anesthesia but had free access to water. All dogs received 2 mg/kg of maropitant PO PO with the study drug 2 hours prior to induction of anesthesia to decrease the incidence of vomiting associated with opioid administration. Dogs were premedicated with 0.1 mg/kg of hydromorphone IM. A 20-gauge IV catheter was then placed in a cephalic vein following aseptic preparation of the skin. Dogs were preoxygenated with a face mask during catheter placement. Anesthesia was induced with propofol administered IV and titrated to effect. After endotracheal intubation, anesthesia was maintained using isoflurane delivered in oxygen with a rebreathing circuit and anesthesia machine. The following physiologic parameters were measured during anesthesia: heart rate, respiratory rate, end-tidal carbon dioxide partial pressure, pulse oximetry, Doppler blood pressure, and body temperature.

After instrumentation, fur was clipped from the ventral abdomen and prepared for ovariohysterectomy via a ventral midline approach. During surgery, heat support was provided to all dogs using a forced warm air blanket to maintain normal body temperature. At the end of anesthesia and after extubation, all dogs were allowed to recover with heat support until they reached a body temperature ≥ 36.7 °C. Full recovery from anesthesia was considered when all of the following criteria were met: the endotracheal tube was removed, body temperature was ≥ 36.7 °C, and the dog was ambulatory. After recovery, the IV catheter was removed and the animals returned to the housing area. Anesthesia time was recorded as the time from propofol administration to discontinuation of isoflurane, and surgery time was recorded as the time from skin incision to the last skin suture.

Pain assessment

Pain assessment and MNT were performed prior to study drug administration (tbaseline), at extubation (t0), and 2, 4, 6, 8, 18, and 24 hours postextubation (t2, t4, t6, t8, t18, t24, respectively). Pain assessment with the GCPS-SF was performed prior to any patient handling at all time points to allow evaluation of the dog while it was undisturbed.

Following completion of the GCPS-SF, MNT assessment was performed using 2 methods. Mechanical nociceptive testing was assessed first with Semmes-Weinstein von Frey filaments (vF; San Diego Instruments Inc). Filaments were applied 2 cm from the incision at 3 locations: the cranial, middle, and caudal aspects of the incision. Filaments were also applied over the caudodorsal flank just cranial to the ilial wing to assess the dogs natural response to MNT. For each measurement, the smallest filament of 0.008 g (0.00008 Pa) was used first to apply mechanical pressure to the area. If enough pressure was applied to cause the filament to bend without a positive reaction from the dog, a sequentially larger filament up to 300 g (2.94 Pa) was used until a positive response was elicited. Vocalization, head turning, or attempts to bite were considered positive responses to mechanical stimulation. At each time point, MNT testing with vF was performed in triplicate at each location and scores were averaged and recorded. Following vF assessments, an algometer (SBMEDIC Electronics) was used to assess MNT in the same locations as vF measurements, 2 cm from the incision and on the flank. The algometer had a 1-cm2 probe and was applied at a slope of 10 kPa/s until the dog elicited a positive response (as listed above) or until a maximum pressure of 100 kPa was reached. Pain scoring was completed, and MNT assessment was performed in this order for all patients at each time point.

Dogs received rescue analgesia (hydromorphone, 0.05 mg/kg, IM) if GCPS-SF scores were ≥ 5/24. Any dog requiring rescue analgesia was reassessed for pain 1 hour after hydromorphone administration using the GCPS-SF. The number of dogs requiring rescue analgesia was recorded, and the animals were evaluated with GCPS-SF for the remainder of the study; however, the pain assessment data from these dogs were not included in the statistical analysis. One investigator masked to the assigned treatment (JMR) performed all pain scoring and MNT at all time points, while handling of the dogs for MNT at all time points was performed by another investigator (EH) masked to treatment assignment.

Statistical analysis

The noninferiority limit for vF was determined using previously published data, which reported Δ = –0.2.14 The analysis of this data is represented graphically and shows the mean difference between grapiprant and carprofen for any 1 given hour from t2 to t24. The mean difference was calculated by subtracting the mean vF for grapiprant from the mean vF of carprofen. Noninferiority was shown if the lower limit of the 95% CI for the difference between treatments was greater than the noninferiority margin (Δ = –0.2).2 For GCPS-SF, a noninferiority margin was set as 3 on the basis of clinical relevance in a change in score of this magnitude. Post hoc power analysis revealed that the sample size was adequate to determine noninferiority with Δ = 3, α = 0.05, and β = 0.2. The data for this value is also represented graphically and is the mean difference between grapiprant and carprofen for any given hour. The mean GCPS-SF for grapiprant minus the mean GCPS-SF for carprofen was used to calculate the mean difference. As the noninferiority limit is positive and lower GCPS-SF scores are indicative of analgesia, noninferiority was shown if the upper limit of the CI for the mean difference between treatments was below the NI margin. Noninferiority was not evaluated for algometry data as there is no literature on this device and no accepted clinically relevant analgesic intervention threshold is known for this device.

Following determination of noninferiority, a mixed-effect ANOVA was used to analyze the effect of treatment group, time, and treatment by time interaction, with treatment as the between-subject factor and time as the within-subject factor. The Tukey correction method was used to find the least-squares means. Shapiro-Wilk plots were used to evaluate normality. A Levene test was used to assess the equality of variances for the residuals.

Surgery and anesthesia times were compared between treatment groups and between surgeons. A Mann-Whitney U test was used to compare variables due to non-normality of anesthesia and surgery times (JMP version 9.4; SAS Institute Inc). Parametric data are reported as mean ± SD, and nonparametric data are presented as median ± IQR. Significance was set at P < .05.

Results

From the 42 dogs enrolled in the study, 3 were excluded. One dog did not eat the study drug, and 2 dogs received rescue hydromorphone. There was no difference in body weight (P = .61), age (P = .88), PCV (P = .59), total solids (P = .72), or blood glucose concentration (P = .51) between treatment groups. For all dogs, median anesthesia time was 40 minutes (IQR, 35 to 45) and median surgical time was 20 minutes (IQR, 15 to 22.5). There was no difference between surgery (P = .67) or anesthesia times (P = .23) between treatment groups. There was also no difference in surgery time between surgeons (P = .86). There was, however, a difference between surgeons in anesthesia time (P < .05). Median anesthesia time for one surgeon was 45 minutes (IQR, 35 to 45) versus 35 minutes (IQR, 35 to 40) for the second surgeon.

The 3 dogs that were excluded from the study were in treatment group GRAP. One dog that received rescue hydromorphone had a GCPS-SF of 5/24 at t2, and the other dog had a GCPS-SF of 6/24 at t2. Both dogs had a GCPS-SF of 1/24 at t0 and a reduction in the GCPS-SF to < 5/24 following administration of hydromorphone. Therefore, data for a total of 39 dogs were statistically analyzed.

The results of the noninferiority analyses are presented (Table 1). The upper limit of the 95% CI for GCPS-SF is represented graphically (Figure 1). Given that the upper limit of the CI is below the noninferiority margin, grapiprant was determined to be noninferior to carprofen when assessed with GCPS-SF. The GCPS-SF was highest at t2, and therefore the mean difference of GCPS-SF values between grapiprant and carprofen was analyzed and presented separately (Table 1). At this time point, grapiprant was noninferior compared to carprofen. Analysis of GCPS-SF revealed that neither the effect of treatment nor treatment by time were significant (P = .89 and P = .62, respectively). The GCPS-SF score changed over time regardless of treatment, and therefore time was the only significant factor (Figure 2). Dogs in both groups had higher GCPS-SF scores at t0, t2, t4, and t6 (P < .01 for all listed time points) when compared with tbaseline. Additionally, dogs in treatment GRAP had higher GCPS-SF scores at t8 (P< .01) when compared with tbaseline. However, GCPS-SF for GRAP was not different at this time point when compared to CAR.

Table 1

Results for GCPS-SF and MNT at the level of the incision at 2, 4, 6, 8, 18, and 24 hours postextubation in 39 dogs undergoing ovariohysterectomy randomly assigned to receive either grapiprant (GRAP, 2 mg/kg; n = 21) or carprofen (CAR, 4.4 mg/kg; 18) PO, 2 hours prior to premedication.

Variable GRAP (SE) CAR (SE) MD SED LCI UCI Delta
GCPS-SF 0.084 0.101 –0.017 0.11 –0.023 0.198 3
GCPS-SF T2 0.143 0.246 0.024 –0.103 –0.263 0.215 3
von Frey (Pa) 0.04 0.054 0.03 0.04 –0.075 –0.004 –0.2
von Frey (size) 0.021 0.038 –0.039 –0.017 N/A N/A N/A
Algometer (kPa) 1.1 0.1 0.72 1.19 –1.61 3.06 N/A

GCPS-SF = Glasgow Composite Pain Scale–Short Form. LCI = Lower limit of the CI. MD = Mean difference. MNT = Mechanical nociceptive threshold. SED = Standard error difference. UCI = Upper limit of the CI.

Figure 1
Figure 1

Graphs depicting the mean difference (small dotted line) along with the 95% CI between grapiprant and carprofen. Larger dashed lines indicate the noninferiority margin. A—GCPS-SF scores are averaged from t2 to t24. B—GCPS-SF scores for only t2.

Citation: Journal of the American Veterinary Medical Association 261, 1; 10.2460/javma.22.08.0353

Figure 2
Figure 2

Mean ± SD GCPS-SF for 39 dogs receiving 1 of 2 treatments (carprofen, 4.4 mg/kg [solid line] or grapiprant, 2 mg/kg [dashed line]) 2 hours prior to surgery (tbaseline), at extubation (t0), and 2, 4, 6, 8, 18, and 24 hours postextubation. *Within the carprofen group, value differs significantly from tbaseline. †Within the grapiprant treatment group, value differs significantly from tbaseline (P < .05).

Citation: Journal of the American Veterinary Medical Association 261, 1; 10.2460/javma.22.08.0353

Noninferiority data for the incisional vF measurements are also presented (Table 1). The lower CI for the mean difference was greater than the noninferiority margin (Figure 3), indicating noninferiority of grapiprant as compared to carprofen. Treatment, treatment by time, and time were not significant when vF filaments were applied to the ventral abdomen (P = .61, P = .61, and P = .09, respectively) or the flank (P = .29, P = .31, P = .31, respectively; Figure 4). Additionally, neither treatment nor treatment by time were significantly different when the algometer was applied to the ventral abdomen (P = .88 and P = .86) or the flank (P = .27 and P = .30). In the treatment group CAR, the algometer values were lower on the ventral abdomen at t4 (P < .01), t6 (P < .01), t8 (P = .02), and t18 (P = .03) when compared with tbaseline. In the treatment group GRAP, algometry values from the ventral abdomen were lower only at t6 (P =.02) when compared with tbaseline (Figure 5).

Figure 3
Figure 3

Graphs depicting the mean difference (small dotted line) in von Frey scores, averaged from 2 to 24 hours postextubation, along with the 95% CI between grapiprant and carprofen. Larger dashed lines indicate the noninferiority margin.

Citation: Journal of the American Veterinary Medical Association 261, 1; 10.2460/javma.22.08.0353

Figure 4
Figure 4

Mean ± SD von Frey scores for 39 dogs receiving 1 of 2 treatments (carprofen, 4.4 mg/kg [solid line] or grapiprant, 2 mg/kg [dashed line]) 2 hours prior to surgery (tbaseline), at extubation (t0), and 2, 4, 6, 8, 18, and 24 hours postextubation.

Citation: Journal of the American Veterinary Medical Association 261, 1; 10.2460/javma.22.08.0353

Figure 5
Figure 5

Mean ± SD algometer scores for 39 dogs receiving 1 of 2 treatments (carprofen, 4.4 mg/kg [solid line] or grapiprant, 2 mg/kg [dashed line]) 2 hours prior to surgery (tbaseline), at extubation (t0), and 2, 4, 6, 8, 18, and 24 hours postextubation. *Within the carprofen group, value differs significantly from tbaseline. †Within the grapiprant treatment group, value differs significantly from tbaseline (P < .05).

Citation: Journal of the American Veterinary Medical Association 261, 1; 10.2460/javma.22.08.0353

Discussion

In the present study, on the basis of GCPS-SF pain scoring and MNT with vF, grapiprant was determined to be noninferior to carprofen at decreasing postsurgical pain following ovariohysterectomy. Thus, we rejected the null hypothesis, which stated that grapiprant would be less efficacious than carprofen in producing postoperative analgesia in healthy dogs undergoing ovariohysterectomy.

Glasgow Composite Pain Scale scores for 39 dogs were < 5/24 at all time points, indicating that a majority of dogs in both groups were comfortable postoperatively. Of the 3 dogs that were excluded, the 2 dogs that required rescue analgesia were from the GRAP group. All other dogs within this group had a GCPS-SF of < 3/24 at t2, indicating that grapiprant provided effective analgesia to the majority of dogs within this population. Additionally, previous studies have investigated the incidence of treatment failure of traditional NSAIDs using GCPS-SF. Friton et al15 assessed the clinical efficacy of preoperative administration of robenacoxib compared to placebo. Treatment failure occurred in only 26.3% of the robenacoxib group, compared to 41.9% failure within the placebo group. A similar study16 compared analgesic efficacy of oral administration of robenacoxib with placebo and found that treatment failure occurred in 23.28% of the robenacoxib group and 35.65% of the placebo group. Compared to these studies, failure rate was much lower in the current study (8.70%). The treatment failure rate for all dogs enrolled in the study was 7.14%, and overall the majority of dogs in this study were comfortable postoperatively. Therefore, our study would suggest grapiprant is an effective perioperative analgesic agent in dogs undergoing ovariohysterectomy. However, it is still recommended that all patients subjected to a noxious stimulus (eg, surgery) are assessed, ideally with a validated pain scoring system, to ensure the therapeutic plan is appropriate.

von Frey filaments were used in this study as a method to characterize the degree to which carprofen and grapiprant affected MNT following surgery. The lack of difference in vF MNT over time and between treatments with this method was important to demonstrate that no dog in the present study developed hyperalgesia. Fitzpatrick et al14 evaluated incisional pain using vF, and, similar to the current study, an area away from the incision was used to control for natural response to the filament and evaluate for the development of allodynia. The results of the latter study were similar to the current study as no dogs in either study developed allodynia. The results of nociceptive threshold testing were also consistent with a previous study by Lascelles et al.4 In that study, the development of hyperalgesia due to central sensitization as a result of surgery were significantly lessened by both preoperative and postoperative administration of carprofen. While the present study did not have a control group, grapiprant was shown to be as effective in preventing hyperalgesia and allodynia as carprofen. No dog in either group developed hyperalgesia or allodynia.

Pressure algometry was used to assess hyperalgesia and incisional pain. While this device has not been validated in veterinary medicine, results of the algometry data in the present study demonstrated an expected distribution of MNT values with a postsurgical decrease in MNT from baseline, which returned to baseline at 24 hours in both treatments. Additionally, the clinical utility of pressure algometry has been reported in dogs.1719 Tallant et al17 evaluated postoperative pain scores using the GCPS-SF and pressure algometry in shelter dogs undergoing ovariectomy compared with ovariohysterectomy, while the other study18 used algometry to compare the postoperative efficacy of 2 analgesics. Both of these studies reported that algometry was useful in assessing postoperative pain.17,18 In contrast, Coleman et al19 found that in normal dogs with no surgical incision, use of an algometer over time has been shown to require less force to elicit a reaction as a result of associated learning. A possible reason for differences in the findings from the Coleman et al study19 compared to our study and others17,18 is the use of dogs without surgical incision compared to the present study and others in which dogs underwent a surgical procedure. A second possible difference is the use of different algometers among studies. The algometer used in Coleman et al19 made an audible beep at the start of each test, and 12 different sites were tested in triplicate for each subject. The present study only used 2 anatomic sites in triplicate for each reading, and our algometer did not condition the dogs to impending manipulation as no “beep” was made at the beginning of each test. Ultimately, inferences regarding the validity of algometry readings cannot be made across studies with differing methodology. Therefore, the algometry results indicated that MNT thresholds decreased over time following ovariohysterectomy and incisional pain was present. There was, however, no significant difference between the 2 treatment groups.

Carprofen was selected as a positive control for this study due to its documented analgesic efficacy in dogs and cats undergoing ovariohysterectomy. Shih et al2 compared the analgesic effects of buprenorphine, carprofen, and buprenorphine plus carprofen in dogs undergoing ovariohysterectomy. All treatment groups provided satisfactory analgesia for the first 24 hours; however, carprofen plus buprenorphine and carprofen alone were superior to buprenorphine alone. When compared with a placebo control, carprofen administered to dogs pre- and postoperatively for routine ovariohysterectomy revealed significantly lower pain scores postoperatively and also reduced central sensitization from surgery-associated pain.4

Carprofen is commercially available and labeled for oral and subcutaneous administration. A study20 comparing the bioequivalence of these 2 formulations of carprofen demonstrated that a single dose administered PO resulted in higher peak plasma concentrations and achieved peak plasma concentrations faster when compared to SC administration. Grapiprant, however, is only available in an oral tablet formulation at this time. Studies of the bioavailability of grapiprant show the oral formulation has better bioavailability when administered to fasted dogs compared with fed dogs or dogs receiving an experimental IV formulation.21 Overall, both drugs have excellent bioavailability after oral administration. Administering both of the study drugs as oral formulations resulted in a consistent method of administration and enabled implementing a masked design while providing optimal bioavailability.

Within the first 24 hours postoperatively, no dogs from either treatment group demonstrated clinical signs of adverse effects associated with NSAID administration. This was expected since grapiprant and carprofen’s safety profiles are well established. In safety studies, carprofen was administered to healthy Beagle dogs at 1, 3, and 5 times the recommended total daily dose for 42 consecutive days with no significant adverse reactions.22 Rausch-Derra et al12 administered doses of grapiprant up to 25 times the therapeutic dose for 9 months without any clinical signs severe enough to warrant medical intervention. During this 9-month study, routine blood and urine laboratory testing revealed no significant changes in liver, kidney, or coagulation function, and necropsy examination of the dogs after completion of the study confirmed unremarkable gross and histologic findings for the liver, kidney, and stomach. While there is minimal evidence comparing safety of grapiprant to traditional COX-selective NSAIDs, grapiprant may offer an attractive alternative to preoperative traditional NSAID therapy in dogs for which NSAID-associated adverse effects are a concern.

The results of the present study demonstrated that grapiprant resulted in noninferior analgesic efficacy to carprofen, and no difference in pain scores or MNT results were detected. These results are in conflict with those reported in a previous study,23 which found grapiprant to be less efficacious in treating inflammatory pain in dogs with experimentally induced sodium urate synovitis when compared with carprofen. One reason for this discrepancy can be attributed to the marked inflammation and pain caused by IA sodium urate administration. Arthropathies due to urate crystallization are well described in human medicine and reported to be extremely painful.24 While ovariohysterectomy may also cause significant pain, the surgeons performing surgeries in this study had extensive experience and tissue trauma was likely minimal. Additionally, unlike the dogs in the synovitis study, the dogs undergoing ovariohysterectomy in this study all received a single preoperative dose of the opioid hydromorphone. The combination of an opioid and NSAID likely provided more potent analgesia than grapiprant alone. Therefore, the explanation for the discrepancy in these studies is likely either the etiology of inflammatory pain or differences in analgesic protocols.

Limitations of this study included the use of a parallel study design instead of a crossover design. A parallel study design limited our ability to assess intrasubject variability. In addition, this study assessed comparable efficacy of grapiprant to carprofen by use of a noninferiority trial instead of a superiority trial. Using a superiority trial would have better assessed a difference between treatments; however, a noninferiority active control study design was used due to ethical concerns of incorporating a placebo or a no-treatment control group. KuKanich et al25 suggested a placebo arm is unnecessary in studies with similar outcome measures due to a high percentage of dogs in negative control groups across multiple studies requiring rescue analgesia, further justifying the exclusion of a placebo group. The third limitation in this study was the use of this model of algometer. To the authors’ knowledge, we are the first to report the use of this device to assess wound sensitivity and hyperalgesia in dogs undergoing ovariohysterectomy. Nevertheless, algometry is a validated method of quantifying mechanical pain threshold and tolerance in humans.26 Additionally, a pain scale validated for use in dogs was used in parallel to algometry to confirm and contrast the results. The final limitation of this study was that the surgeons performing ovariohysterectomies had extensive experience with this procedure and tissue trauma was likely minimal. Therefore, these results should not be inferred in dogs with more significant soft tissue injury and secondary inflammation. However, multiple studies have reported the necessity of analgesia for dogs undergoing ovariohysterectomy despite the routine nature of the procedure.18,2730

To our knowledge, this study was the first to evaluate the efficacy of grapiprant to control acute soft tissue inflammatory pain. The results of this study indicate that grapiprant represents an effective analgesic alternative to carprofen in dogs undergoing elective ovariohysterectomy. Additionally, the results support the preoperative use of grapiprant as an alternative to traditional NSAIDs for mitigating ovariohysterectomy-induced hyperalgesia and allodynia.

Acknowledgments

This study was funded by a University of Tennessee Companion Animal Fund grant (grant award No. 2021.04).

Statistical analysis was provided by Xiaojuan Zhu.

References

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    KuKanich B, Bidgood T, Knesl O. Clinical pharmacology of nonsteroidal anti-inflammatory drugs in dogs. Vet Anaesth Analg. 2012;39(1):6990.

  • 2.

    Shih AC, Robertson S, Isaza N, Pablo L, Davies W. Comparison between analgesic effects of buprenorphine, carprofen, and buprenorphine with carprofen for canine ovariohysterectomy. Vet Anaesth Analg. 2008;35(1):6979.

    • PubMed
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    Bergh MS, Budsberg SC. The coxib NSAIDs: potential clinical and pharmacologic importance in veterinary medicine. J Vet Intern Med. 2005;19(5):633643.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Lascelles BD, Cripps PJ, Jones A, Waterman-Pearson AE. Efficacy and kinetics of carprofen, administered preoperatively or postoperatively, for the prevention of pain in dogs undergoing ovariohysterectomy. Vet Surg. 1998;27(6):568582.

    • Search Google Scholar
    • Export Citation
  • 5.

    Leece EA, Brearley JC, Harding EF. Comparison of carprofen and meloxicam for 72 hours following ovariohysterectomy in dogs. Vet Anaesth Analg. 2005;32(4):184192.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Monteiro-Steagall BP, Steagall PV, Lascelles BD. Systematic review of nonsteroidal anti-inflammatory drug-induced adverse effects in dogs (Erratum published in J Vet Intern Med. 2014;28[2]:745). J Vet Intern Med. 2013;27(5):10111019.

    • Search Google Scholar
    • Export Citation
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    Neiger R. NSAID-induced gastrointestinal adverse effects in dogs–can we avoid them? J Vet Intern Med. 2003;17(3):259261.

  • 8.

    Nakao K, Murase A, Ohshiro H, et al. CJ-023,423, a novel, potent and selective prostaglandin EP4 receptor antagonist with antihyperalgesic properties. J Pharmacol Exp Ther. 2007;322(2):686694.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Ma W, St-Jacques B. Signalling transduction events involved in agonist-induced PGE2/EP4 receptor externalization in cultured rat dorsal root ganglion neurons. Eur J Pain. 2018;22(5):845861.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Rausch-Derra L, Huebner M, Wofford J, Rhodes L. A prospective, randomized, masked, placebo-controlled multisite clinical study of grapiprant, an EP4 prostaglandin receptor antagonist (PRA), in dogs with osteoarthritis. J Vet Intern Med. 2016;30(3):756763.

    • PubMed
    • Search Google Scholar
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  • 11.

    Nagahisa A, Okumura T. Pharmacology of grapiprant, a novel EP4 antagonist: receptor binding, efficacy in a rodent postoperative pain model, and a dose estimation for controlling pain in dogs. J Vet Pharmacol Ther. 2017;40(3):285292.

    • Search Google Scholar
    • Export Citation
  • 12.

    Rausch-Derra LC, Huebner M, Rhodes L. Evaluation of the safety of long-term, daily oral administration of grapiprant, a novel drug for treatment of osteoarthritic pain and inflammation, in healthy dogs. Am J Vet Res. 2015;76(10):853859.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Reid J, Nolan A, Hughes J. Development of the short-form Glasgow Composite Measure Pain Scale (CMPS-SF) and derivation of an analgesic intervention score. Anim Welf. 2007;16(suppl 1):97104.

    • Search Google Scholar
    • Export Citation
  • 14.

    Fitzpatrick CL, Weir HL, Monnet E. Effects of infiltration of the incision site with bupivacaine on postoperative pain and incisional healing in dogs undergoing ovariohysterectomy. J Am Vet Med Assoc. 2010;237(4):395401.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Friton G, Thompson C, Karadzovska D, King S, King JN. Efficacy and safety of injectable robenacoxib for the treatment of pain associated with soft tissue surgery in dogs. J Vet Intern Med. 2017;31(3):832841.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Friton G, Thompson CM, Karadzovska D, King S, King JN. Efficacy and safety of oral robenacoxib (tablet) for the treatment of pain associated with soft tissue surgery in client-owned dogs. BMC Vet Res. 2017;13(1):197197.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Tallant A, Ambros B, Freire C, Sakals S. Comparison of intraoperative and postoperative pain during canine ovariohysterectomy and ovariectomy. Can Vet J. 2016;57(7):741746.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Kalchofner Guerrero KS, Schwarz A, Wuhrmann R, Feldmann S, Hartnack S, Bettschart-Wolfensberger R. Comparison of a new metamizole formulation and carprofen for extended post-operative analgesia in dogs undergoing ovariohysterectomy. Vet J. 2015;204(1):99104.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Coleman KD, Schmiedt CW, Kirkby KA, et al. Learning confounds algometric assessment of mechanical thresholds in normal dogs. Vet Surg. 2014;43(3):361367.

  • 20.

    Clark TP, Chieffo C, Huhn JC, Nimz EL, Wang C, Boy MG. The steady-state pharmacokinetics and bioequivalence of carprofen administered orally and subcutaneously in dogs. J Vet Pharmacol Ther. 2003;26(3):187192.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Łebkowska-Wieruszewska B, Barsotti G, Lisowski A, Gazzano A, Owen H, Giorgi M. Pharmacokinetics and estimated bioavailability of grapiprant, a novel selective prostaglandin E2 receptor antagonist, after oral administration in fasted and fed dogs. N Z Vet J. 2017;65(1):1923.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Rimadyl (carprofen). Package insert. Zoetis; 2019.

  • 23.

    Budsberg SC, Kleine SA, Norton MM, Sandberg GS. Comparison of two inhibitors of E-type prostanoid receptor four and carprofen in dogs with experimentally induced acute synovitis. Am J Vet Res. 2019;80(11):10011006.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Weaver JS, Vina ER, Munk PL, Klauser AS, Elifritz JM, Taljanovic MS. Gouty arthropathy: review of clinical manifestations and treatment, with emphasis on imaging. J Clin Med. 2021;11(1):166. doi:10.3390/jcm11010166

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    KuKanich B, KuKanich K, Rankin DC, et al. Perioperative analgesia associated with oral administration of a novel methadone-fluconazole-naltrexone formulation in dogs undergoing routine ovariohysterectomy. Am J Vet Res. 2020;81(9):699707.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Hsu YW, Somma J, Hung YC, Tsai PS, Yang CH, Chen CC. Predicting postoperative pain by preoperative pressure pain assessment. Anesthesiology. 2005;103(3):613618.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Bustamante R, Daza MA, Canfrán S, et al. Comparison of the postoperative analgesic effects of cimicoxib, buprenorphine and their combination in healthy dogs undergoing ovariohysterectomy. Vet Anaesth Analg. 2018;45(4):545556.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Morgaz J, Navarrete R, Muñoz-Rascón P, et al. Postoperative analgesic effects of dexketoprofen, buprenorphine and tramadol in dogs undergoing ovariohysterectomy. Res Vet Sci. 2013;95(1):278282.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Watanabe R, Monteiro BP, Evangelista MC, Castonguay A, Edge D, Steagall PV. The analgesic effects of buprenorphine (Vetergesic or Simbadol) in combination with carprofen in dogs undergoing ovariohysterectomy: a randomized, blinded, clinical trial. BMC Vet Res. 2018;14(1):304. doi:10.1186/s12917-018-1628-4

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Bienhoff SE, Smith ES, Roycroft LM, Roberts ES, Baker LD. Efficacy and safety of deracoxib for the control of postoperative pain and inflammation associated with dental surgery in dogs. ISRN Vet Sci. 2012;2011:593015. doi:10.5402/2011/593015

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Figure 1

    Graphs depicting the mean difference (small dotted line) along with the 95% CI between grapiprant and carprofen. Larger dashed lines indicate the noninferiority margin. A—GCPS-SF scores are averaged from t2 to t24. B—GCPS-SF scores for only t2.

  • Figure 2

    Mean ± SD GCPS-SF for 39 dogs receiving 1 of 2 treatments (carprofen, 4.4 mg/kg [solid line] or grapiprant, 2 mg/kg [dashed line]) 2 hours prior to surgery (tbaseline), at extubation (t0), and 2, 4, 6, 8, 18, and 24 hours postextubation. *Within the carprofen group, value differs significantly from tbaseline. †Within the grapiprant treatment group, value differs significantly from tbaseline (P < .05).

  • Figure 3

    Graphs depicting the mean difference (small dotted line) in von Frey scores, averaged from 2 to 24 hours postextubation, along with the 95% CI between grapiprant and carprofen. Larger dashed lines indicate the noninferiority margin.

  • Figure 4

    Mean ± SD von Frey scores for 39 dogs receiving 1 of 2 treatments (carprofen, 4.4 mg/kg [solid line] or grapiprant, 2 mg/kg [dashed line]) 2 hours prior to surgery (tbaseline), at extubation (t0), and 2, 4, 6, 8, 18, and 24 hours postextubation.

  • Figure 5

    Mean ± SD algometer scores for 39 dogs receiving 1 of 2 treatments (carprofen, 4.4 mg/kg [solid line] or grapiprant, 2 mg/kg [dashed line]) 2 hours prior to surgery (tbaseline), at extubation (t0), and 2, 4, 6, 8, 18, and 24 hours postextubation. *Within the carprofen group, value differs significantly from tbaseline. †Within the grapiprant treatment group, value differs significantly from tbaseline (P < .05).

  • 1.

    KuKanich B, Bidgood T, Knesl O. Clinical pharmacology of nonsteroidal anti-inflammatory drugs in dogs. Vet Anaesth Analg. 2012;39(1):6990.

  • 2.

    Shih AC, Robertson S, Isaza N, Pablo L, Davies W. Comparison between analgesic effects of buprenorphine, carprofen, and buprenorphine with carprofen for canine ovariohysterectomy. Vet Anaesth Analg. 2008;35(1):6979.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Bergh MS, Budsberg SC. The coxib NSAIDs: potential clinical and pharmacologic importance in veterinary medicine. J Vet Intern Med. 2005;19(5):633643.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Lascelles BD, Cripps PJ, Jones A, Waterman-Pearson AE. Efficacy and kinetics of carprofen, administered preoperatively or postoperatively, for the prevention of pain in dogs undergoing ovariohysterectomy. Vet Surg. 1998;27(6):568582.

    • Search Google Scholar
    • Export Citation
  • 5.

    Leece EA, Brearley JC, Harding EF. Comparison of carprofen and meloxicam for 72 hours following ovariohysterectomy in dogs. Vet Anaesth Analg. 2005;32(4):184192.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Monteiro-Steagall BP, Steagall PV, Lascelles BD. Systematic review of nonsteroidal anti-inflammatory drug-induced adverse effects in dogs (Erratum published in J Vet Intern Med. 2014;28[2]:745). J Vet Intern Med. 2013;27(5):10111019.

    • Search Google Scholar
    • Export Citation
  • 7.

    Neiger R. NSAID-induced gastrointestinal adverse effects in dogs–can we avoid them? J Vet Intern Med. 2003;17(3):259261.

  • 8.

    Nakao K, Murase A, Ohshiro H, et al. CJ-023,423, a novel, potent and selective prostaglandin EP4 receptor antagonist with antihyperalgesic properties. J Pharmacol Exp Ther. 2007;322(2):686694.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Ma W, St-Jacques B. Signalling transduction events involved in agonist-induced PGE2/EP4 receptor externalization in cultured rat dorsal root ganglion neurons. Eur J Pain. 2018;22(5):845861.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Rausch-Derra L, Huebner M, Wofford J, Rhodes L. A prospective, randomized, masked, placebo-controlled multisite clinical study of grapiprant, an EP4 prostaglandin receptor antagonist (PRA), in dogs with osteoarthritis. J Vet Intern Med. 2016;30(3):756763.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Nagahisa A, Okumura T. Pharmacology of grapiprant, a novel EP4 antagonist: receptor binding, efficacy in a rodent postoperative pain model, and a dose estimation for controlling pain in dogs. J Vet Pharmacol Ther. 2017;40(3):285292.

    • Search Google Scholar
    • Export Citation
  • 12.

    Rausch-Derra LC, Huebner M, Rhodes L. Evaluation of the safety of long-term, daily oral administration of grapiprant, a novel drug for treatment of osteoarthritic pain and inflammation, in healthy dogs. Am J Vet Res. 2015;76(10):853859.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Reid J, Nolan A, Hughes J. Development of the short-form Glasgow Composite Measure Pain Scale (CMPS-SF) and derivation of an analgesic intervention score. Anim Welf. 2007;16(suppl 1):97104.

    • Search Google Scholar
    • Export Citation
  • 14.

    Fitzpatrick CL, Weir HL, Monnet E. Effects of infiltration of the incision site with bupivacaine on postoperative pain and incisional healing in dogs undergoing ovariohysterectomy. J Am Vet Med Assoc. 2010;237(4):395401.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Friton G, Thompson C, Karadzovska D, King S, King JN. Efficacy and safety of injectable robenacoxib for the treatment of pain associated with soft tissue surgery in dogs. J Vet Intern Med. 2017;31(3):832841.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Friton G, Thompson CM, Karadzovska D, King S, King JN. Efficacy and safety of oral robenacoxib (tablet) for the treatment of pain associated with soft tissue surgery in client-owned dogs. BMC Vet Res. 2017;13(1):197197.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Tallant A, Ambros B, Freire C, Sakals S. Comparison of intraoperative and postoperative pain during canine ovariohysterectomy and ovariectomy. Can Vet J. 2016;57(7):741746.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Kalchofner Guerrero KS, Schwarz A, Wuhrmann R, Feldmann S, Hartnack S, Bettschart-Wolfensberger R. Comparison of a new metamizole formulation and carprofen for extended post-operative analgesia in dogs undergoing ovariohysterectomy. Vet J. 2015;204(1):99104.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Coleman KD, Schmiedt CW, Kirkby KA, et al. Learning confounds algometric assessment of mechanical thresholds in normal dogs. Vet Surg. 2014;43(3):361367.

  • 20.

    Clark TP, Chieffo C, Huhn JC, Nimz EL, Wang C, Boy MG. The steady-state pharmacokinetics and bioequivalence of carprofen administered orally and subcutaneously in dogs. J Vet Pharmacol Ther. 2003;26(3):187192.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Łebkowska-Wieruszewska B, Barsotti G, Lisowski A, Gazzano A, Owen H, Giorgi M. Pharmacokinetics and estimated bioavailability of grapiprant, a novel selective prostaglandin E2 receptor antagonist, after oral administration in fasted and fed dogs. N Z Vet J. 2017;65(1):1923.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Rimadyl (carprofen). Package insert. Zoetis; 2019.

  • 23.

    Budsberg SC, Kleine SA, Norton MM, Sandberg GS. Comparison of two inhibitors of E-type prostanoid receptor four and carprofen in dogs with experimentally induced acute synovitis. Am J Vet Res. 2019;80(11):10011006.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Weaver JS, Vina ER, Munk PL, Klauser AS, Elifritz JM, Taljanovic MS. Gouty arthropathy: review of clinical manifestations and treatment, with emphasis on imaging. J Clin Med. 2021;11(1):166. doi:10.3390/jcm11010166

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    KuKanich B, KuKanich K, Rankin DC, et al. Perioperative analgesia associated with oral administration of a novel methadone-fluconazole-naltrexone formulation in dogs undergoing routine ovariohysterectomy. Am J Vet Res. 2020;81(9):699707.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Hsu YW, Somma J, Hung YC, Tsai PS, Yang CH, Chen CC. Predicting postoperative pain by preoperative pressure pain assessment. Anesthesiology. 2005;103(3):613618.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Bustamante R, Daza MA, Canfrán S, et al. Comparison of the postoperative analgesic effects of cimicoxib, buprenorphine and their combination in healthy dogs undergoing ovariohysterectomy. Vet Anaesth Analg. 2018;45(4):545556.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Morgaz J, Navarrete R, Muñoz-Rascón P, et al. Postoperative analgesic effects of dexketoprofen, buprenorphine and tramadol in dogs undergoing ovariohysterectomy. Res Vet Sci. 2013;95(1):278282.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Watanabe R, Monteiro BP, Evangelista MC, Castonguay A, Edge D, Steagall PV. The analgesic effects of buprenorphine (Vetergesic or Simbadol) in combination with carprofen in dogs undergoing ovariohysterectomy: a randomized, blinded, clinical trial. BMC Vet Res. 2018;14(1):304. doi:10.1186/s12917-018-1628-4

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Bienhoff SE, Smith ES, Roycroft LM, Roberts ES, Baker LD. Efficacy and safety of deracoxib for the control of postoperative pain and inflammation associated with dental surgery in dogs. ISRN Vet Sci. 2012;2011:593015. doi:10.5402/2011/593015

    • PubMed
    • Search Google Scholar
    • Export Citation

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