Introduction
Local anesthetics are unique as the only drug class that renders complete analgesia.1 These drugs produce both sensory and motor blockade by inhibiting the generation and propagation of electrical impulses via blockage of voltage-gated sodium channels, preventing membrane depolarization and nerve conduction.2 Local anesthetics may decrease the need for general anesthetics, provide analgesia during recovery from a surgical procedure, and decrease maladaptive pain states after surgery.1,2 Systemic adverse effects (eg, neurologic or cardiovascular toxicity) are possible but rare in clinical practice and typically only seen with inappropriately high doses or inadvertent intravascular administration.1,2 Local anesthetics are generally considered safe and predictable analgesics in veterinary medicine.1
Local anesthetics have been investigated in veterinary patients for incisional analgesia.3–9 Multiple studies found reduction in postoperative pain behaviors and analgesic requirements after abdominal surgery with these techniques, though conflicting results have been produced.4,5,8,10–12 The World Small Animal Veterinary Association Global Pain Council and American Animal Hospital Association guidelines on pain management in dogs and cats, last updated in 2022, recommend local anesthetics be considered in all surgeries and particularly at incisional sites as part of a multimodal analgesia regimen when possible.1,3,13
A shortcoming of standard local anesthetics is their limited duration of action. A study comparing lidocaine to bupivacaine for incisional and IP analgesia suggested that longer-acting local anesthetics are preferable, but even standard local anesthetics that last several hours do not outlast anticipated incisional pain.2–4 The inflammatory phase of wound healing is expected to occur for 72 hours after surgery, so a longer-acting local anesthetic formulation would be ideal, especially as many animals are discharged from the hospital sooner than 3 days postoperatively.14 A liposome-encapsulated, prolonged-release formulation of bupivacaine has been developed and successfully employed for incisional analgesia for a variety of soft tissue and orthopedic surgeries in people.14,15 A veterinary formulation of liposomal bupivacaine (NOCITA) is now also available. Studies of dogs undergoing stifle surgery found that this product provided local analgesia for 72 hours postoperatively and lowered the incidence of rescue analgesia and postoperative opioid requirements compared to standard bupivacaine.16,17
The label indication for liposomal bupivacaine in veterinary medicine is limited to use for cranial cruciate ligament surgery in dogs and onychectomy in cats, but the authors have used this drug clinically for incisional analgesia for many other orthopedic and soft tissue surgeries at a veterinary referral facility and observed markedly improved postoperative incisional analgesia.18 Ovariohysterectomy is a procedure commonly performed in dogs on an outpatient basis that is associated with a mild to moderate level of pain.8,19,20 At this time, there is no evidence in the veterinary literature to support the use of liposome-encapsulated bupivacaine for abdominal incisions. However, use of the liposome-encapsulated bupivacaine product in human medicine has been described for obstetric and gynecologic surgery.14,21,22
The purpose of this study was to determine whether an infiltrative block with liposomal bupivacaine for incisional analgesia after ovariohysterectomy in a teaching laboratory would result in a lower incidence of rescue analgesia administration and lower pain scores compared to the current standard of care bupivacaine splash block. We hypothesized that dogs that received liposomal bupivacaine would require rescue analgesia at a lower incidence and have lower pain scores compared to those that had received a splash block with standard bupivacaine.
Methods
Animals
All dogs presenting to a low-cost spay/neuter clinic in the Introduction to Small Animal Anesthesia and Surgery Techniques (ISAAST) course (a core requirement for third-year students in the Doctor of Veterinary Medicine curriculum at the Cummings School of Veterinary Medicine) during the study period were eligible for enrollment. The study period lasted 1 academic year of the course from August 2019 to March 2020. Consent for inclusion was obtained from the owner or shelter/rescue organization responsible for each dog. Dogs were required to be no older than 7 years of age and in good general health. Dogs were excluded from enrollment if consent was not obtained. Ethical approval for this study was obtained from the Clinical Studies Review Committee at the Cummings School of Veterinary Medicine. Age, weight, breed, and body condition score (BCS) were recorded for each dog. Body condition scoring (on a scale of 1 to 9) was performed using the Purina Body Condition System.23 Allowable variations (detailed in the methodology) from and unanticipated violations of standard study protocol after enrollment resulted in exclusion from the final data analysis.
Surgery and anesthesia protocol
After enrollment, dogs were randomly assigned to the bupivacaine study group (BUPIV) or liposomal bupivacaine study group (NOCI). Randomization was performed via permuted block randomization with a block size of 10 to maintain treatment balance over the course of the study. No stratification was used in the randomization. After randomization, all dogs underwent general anesthesia and open ovariohysterectomy performed by third-year veterinary students under a supervising veterinarian using the existing protocol in place for the ISAAST course as follows.
Dogs were admitted for hospitalization 1 or 2 days prior to surgery depending on their assigned surgery day, housed in individual kennels, and cared for by third-year veterinary students under the direction of the spay/neuter clinic staff and a supervising veterinarian. Physical exam and preoperative bloodwork (PCV, total solids, blood glucose, and azo test strip) were performed to confirm good health status. On the day of surgery, dogs received premedication IM with hydromorphone (0.1 mg/kg), acepromazine (0.05 mg/kg), and atropine (0.02 mg/kg). After 30 minutes, an IV catheter was placed in the cephalic vein. Anesthesia was induced with propofol administered to effect. Dogs were intubated and maintained under anesthesia with isoflurane in 100% oxygen titrated to maintain a medium depth of anesthesia based on eye position, palpebral reflex, and vital parameters. Fluid therapy with lactated Ringer solution at 10 mL/kg/h IV was initiated. Cefazolin (22 mg/kg) was administered IV over 10 minutes. Patients were monitored using a multiparameter monitor (pulse oximetry, electrocardiography, and capnography), Doppler blood pressure, and an esophageal stethoscope.
After induction, the patient was clipped and sterilely prepped, and an open ovariohysterectomy was performed. At closure, an incisional local block was performed on the basis of group assignment. Administration of blocks in all dogs was performed by a single veterinary technician trained in this technique. Dogs in BUPIV received a splash block with 0.5% bupivacaine (1 mg/kg; 0.2 mL/kg) performed by dripping the entire volume of local anesthetic over the closed body wall prior to closure of the subcutaneous layer. Dogs in NOCI received an infiltrative block with liposomal bupivacaine (5.3 mg/kg; 0.4 mL/kg) performed prior to closure of the linea alba to minimize the risk of inadvertent IP injection, which could result in trauma to abdominal organs.6 For the infiltrative block, a moving needle technique (in which the needle was inserted nearly to the level of the hub, aspiration was performed to ensure the needle was not intravascular, and the drug was administered as the needle was withdrawn) was used along the entire length of both sides of the incision in the body wall, subcutaneous tissue, and skin layers. After administration of the local block, closure was continued, and dogs were allowed to recover from anesthesia.
At the time of extubation, dogs received an NSAID (carprofen [2 mg/kg], meloxicam [0.1 mg/kg], or robenacoxib [2 mg/kg] based on patient size and drug availability at that time) SC. Carprofen was continued PO twice daily, and meloxicam and robenacoxib were continued PO once daily while dogs were in hospital. Dogs were discharged with sufficient medication to complete a 3-day course of the NSAID. Surgery time, anesthesia time, and time to extubation were recorded for each dog.
Postoperative pain assessment
Dogs were pain scored postoperatively by a single evaluator who was a veterinary anesthesia resident experienced in pain evaluation in veterinary patients. Blinding was accomplished by not allowing the evaluator to be present during surgery while the block was performed, and other laboratory participants were instructed to not inform the evaluator of what treatment the dog received. Pain score evaluation occurred immediately after NSAID administration, which occurred as soon as dogs were extubated (0 to 4 hours after local block administration), and at subsequent time intervals at which patients were scheduled to receive monitoring and basic care treatments as part of the routine functioning of the ISAAST course: 4 to 8 hours (4:00 pm), 8 to 12 hours (9:00 pm), and ≥ 12 hours (6:00 am the next day) after local block administration. All dogs were evaluated at each time point and were not excluded from future assessment if they received a dose of rescue analgesia. Although the exact time of extubation varied due to difference in surgical timing, extubation and the first time point typically occurred between 10:30 am and 12:30 pm and in no instance < 3 hours before the 4:00 pm time point.
All dogs were evaluated at each time point using both the Colorado State University–Canine Acute Pain Scale (CSU-CAPS) and the Glasgow Composite Measures Pain Scale–Short Form (GCPS-SF).24,25 Dogs were first evaluated from outside of their cages for spontaneous behaviors and posture as described in the pain scoring systems. A neck lead was placed on the dog, the dog was removed from the cage, and mobility was assessed by allowing them to walk on the lead. The mobility assessment was not performed at the time of extubation. Assessment of reaction to incisional palpation was performed by applying gentle pressure with a hand in a region far from the incision site and then application of similar pressure around the incision site. Dogs with a score ≥ 2 on the CSU-CAPS received rescue analgesia of buprenorphine (0.01 mg/kg) IV or SC based on catheter patency, and the time of administration of rescue analgesia from the time that the local block was administered was recorded.
Additional postoperative care
If dogs appeared excited after extubation (eg, from opioid dysphoria, emergence delirium, etc), they received dexmedetomidine and/or acepromazine at the discretion of the primary evaluator or supervising veterinarian after their first pain score was performed and they had been first administered analgesia if deemed appropriate.26 Dogs were administered sedation prior to pain assessment if their excitement level risked their own or personnel safety. Dogs that demonstrated signs of gastrointestinal upset (vomiting or nausea) after surgery received maropitant (1 mg/kg) IV or SC based on catheter patency no more frequently than once every 24 hours. Dogs were not administered an NSAID immediately after extubation if they had diarrhea, vomiting, or regurgitation prior to or during surgery and anesthesia. NSAID administration was discontinued if the patient was unwilling to eat when medication was due and/or if maropitant was administered due to vomiting. Additional surgical procedures were performed on dogs during their anesthesia if it was medically indicated for the patient.
Power analysis
Prior to study enrollment, a power analysis was performed and based on an anticipated 200 eligible dogs participating in the teaching laboratory. The primary outcome was defined as the administration of rescue analgesia and the primary analysis as a comparison of the proportion of dogs that receive rescue analgesia between groups. Using a 2-sided likelihood ratio χ2 test with a significance level of 0.05, if the usual care proportion for administration of rescue analgesia was 0.25, the minimum detectable difference lower than the usual care proportion was –0.15 with 80% power and –0.17 with 90% power. If the usual care proportion for administration of rescue analgesia was defined as 0.5, the minimum detectable difference lower than the usual care proportion was –0.19 with 80% power and –0.22 with 90% power. The usual care proportions were estimated on the basis of the clinical experience of the authors with other patients’ postoperative routine abdominal surgeries. Power calculations were performed using standard software (PASS 15 version 15; NCSS).
Statistical analysis
Mean and SD for each group were determined for age, weight, BCS, surgery time, anesthesia time, and time to extubation. Continuous variables with normal distributions were compared between groups using a Student t test.
A χ2 analysis was performed to test for a difference between groups for incidence of rescue analgesia administration (yes/no). A logistic regression model was used to estimate the odds of rescue administration between groups. A Kaplan-Meier time-to-event analysis was used to analyze time to rescue analgesia (from the time of administration of the local block), and a log-rank test was used to evaluate for a difference in time to rescue between groups. Dogs that did not require a rescue analgesia dose were given a rescue time of 720 minutes (12 hours follow-up).
For the secondary outcomes, we tested the longitudinal CSU-CAPS and GCPS-SF scores for normality using 3 tests (Kolmogorov-Smirnov, Cramer-Mises, and Shapiro-Wilk). We tested each pain score at each time point. The results for each score and time point indicated a significant test (P < .01) for all 3 test statistics, indicating nonnormality for each score. Thus, we compared the scores for each outcome between groups over time using a longitudinal logistic regression model. For these secondary outcomes, because of the highly skewed nature of their distribution, we combined the scores to create a binary outcome for each as follows: (1) for the CSU-CAPS score (range, 0 to 3), we coded 0 as none/low and 1 to 3 as elevated; for the GCMPS-SF score (0 to 24), we coded 0, 1, and 2 as none/low and ≥ 3 as elevated. Using this coding system, we applied χ2 analysis and longitudinal logistic regression analysis to determine the effect of local anesthesia type over time. To adjust the OR for other factors, we included age and weight (in addition to local anesthesia type and hours after administration) in the longitudinal logistic regression model, which we fit to the data using generalized estimating equations procedures in SAS statistical software (version 9.4; SAS Institute Inc). The ORs reported here are from the least-squares mean procedure, which, for a logistic regression model, produces OR adjusted for other factors in the model.
We used a nominal P value of .05 as the critical P value in all statistical tests. To control the experiment-wise error rate, we used a gate-keeping approach as suggested by the FDA.27,28 In this controlled testing procedure, the primary outcome (proportion of dogs receiving rescue medication) would be tested first and, if a significant difference was found, the α error was recycled and used to test the secondary outcomes in order of CSU-CAPS followed by GCPS-SF at the α error level of 0.05. If the CSU-CAPS treatment group comparison was not significant, the GCPS-SF test would not be performed. All analyses were performed using standard software (SAS Statistical Software version 9.4; SAS Institute Inc).
Results
Demographic characteristics
A total of 196 dogs were considered for enrollment in the study. Twenty-four dogs were excluded due to declined consent. Eighty-eight patients were allocated to NOCI, and 84 were allocated to BUPIV. No dogs were removed from either intervention after allocation for any reason, and all dogs were evaluated at each time point. One dog in BUPIV did not have a CSU-CAPS score for the first time point due to failure to record this value. Protocol variations that led to exclusion from final data analysis included undergoing an additional surgical procedure, not receiving or discontinuation of an NSAID, receiving postoperative sedation, and receiving postoperative maropitant. Protocol violations included local block performance by an alternative administrator, pain assessment performed by an alternative evaluator, and administration of diphenhydramine IM upon development of urticaria during surgery. With exclusions due to protocol violations and variations, 136 dogs (65 in BUPIV and 71 in NOCI) were included in these analyses. The inclusion and exclusion of dogs in the study by group are detailed elsewhere (Supplementary Figure S1). This flow diagram was adapted from that described by the Consolidated Standards of Reporting Trials Guidelines.29
Dogs enrolled in the study were of a variety of breeds (Supplementary Table S1). There was no significant difference between groups for age, weight, BCS, or time to extubation. There was a significant difference between groups for surgery time (P = .002) and anesthesia time (P = .01; Table 1).
Demographic characteristics for dogs that underwent ovariohysterectomy in a teaching laboratory and were grouped by the incisional analgesia they received, either a bupivacaine splash block (BUPIV) or an infiltrative block with liposomal bupivacaine (NOCI), at the time of closure.
| Characteristic | BUPIV (n = 65) Mean (SD) | NOCI (n = 71) Mean (SD) | P value |
|---|---|---|---|
| Age (y) | 1.59 (1.64) | 1.97 (2.02) | .23 |
| Weight (kg) | 16.03 (7.72) | 16.10 (8.67) | .96 |
| Body condition score (1–9) | 4.73 (0.77) | 4.84 (0.96) | .50 |
| Surgery time (min) | 113.4 (25.15)a | 129.7 (34.44)b | .002 |
| Anesthesia time (min) | 157.1 (28.3)a | 170.8 (35.3)b | .01 |
| Time to extubation (min) | 15.57 (9.55) | 17.48 (11.35) | .30 |
P values were determined using a Student t test. There was no significant difference between groups in age, weight, body condition score, or time to extubation. There was a significant difference in surgery time and anesthesia time between groups.
a–bValues with different superscripts are significantly (P < .05) different.
Rescue analgesia administration—primary outcome
In BUPIV, 23 of 65 (35%) dogs required a dose of rescue analgesia at some time point compared to 14 of 71 (20%) dogs in NOCI (P = .04). Incidence of administration of rescue analgesia by group at each time point is reported (Figure 1). Analysis with a logistic regression model indicated that BUPIV dogs were twice as likely (OR = 2.2; 95% CI, 1.0 to 4.9; P = .045) to need rescue analgesia than NOCI dogs. In terms of cumulative incidence, in NOCI, 1 (1.0%) dog had received rescue medication by 4 hours, 9 (13%) dogs cumulative by 8 hours, and 14 (20%) dogs by 12 hours, with 57 (80%) dogs never receiving any rescue medication. In BUPIV, 6 (9%) dogs had received rescue medication by 4 hours, 17 (26%) dogs by 8 hours, and 23 (35%) dogs by 12 hours, with 42 (65%) dogs never receiving rescue medication.
The percentage of dogs that received rescue analgesia with buprenorphine based on an assigned Colorado State University–Canine Acute Pain Scale (CSU-CAPS) score ≥ 2 at each pain assessment time point after administration of either a bupivacaine splash block (BUPIV) or an infiltrative block with liposomal bupivacaine (NOCI) at the time of closure following performance of open ovariohysterectomy by a veterinary student in a surgical teaching laboratory. In BUPIV, 23 of 65 (35%) dogs required a dose of rescue analgesia at some time point compared to 14 of 71 (20%) dogs in NOCI (P = .04).
Citation: Journal of the American Veterinary Medical Association 261, 11; 10.2460/javma.23.01.0057
As a sensitivity analysis of the primary outcome using a Kaplan-Meier time-to-rescue analgesia analysis, NOCI had a significantly longer (log-rank test P = .03) time before needing rescue analgesia than BUPIV. The median time to administration of rescue analgesia in BUPIV was 385 minutes compared to 425 minutes in NOCI (Figure 2).
The Kaplan-Meier probability of survival (not needing a rescue dose of analgesia) over time of dogs that underwent ovariohysterectomy in a teaching laboratory and were grouped by the incisional anesthesia they received, either BUPIV (blue line) or NOCI (red line), at the time of closure. Dogs that never required a rescue dose of analgesia were assigned a rescue time of 720 minutes (12 hours follow-up). Dogs in NOCI had a significantly longer (log-rank test P = .03) time before needing rescue analgesia than BUPIV. The median time to administration of rescue analgesia in BUPIV was 385 minutes compared to 425 minutes in NOCI.
Citation: Journal of the American Veterinary Medical Association 261, 11; 10.2460/javma.23.01.0057
Pain scores—secondary outcomes
Using a generalized estimating equation longitudinal logistic model to analyze the CSU-CAPS pain scores, there was an overall time-averaged significant treatment group difference of BUPIV compared to NOCI (OR, 1.65; 95% CI, 1.002 to 2.72; P = .049), indicating that dogs in BUPIV were 65% more likely than those in NOCI to experience elevated pain at some point in the postsurgery recovery period. Similarly, for the GCPS-SF pain scores, using the same modeling approach, there was an overall time-averaged significant treatment group difference of BUPIV compared to NOCI (OR, 2.12; 95% CI, 1.21 to 3.77; P = .015), indicating that dogs that received BUPIV were over twice as likely as those that received NOCI to have elevated pain at some point in the postsurgical recovery period (Figure 3). As noted in the Methods, we used a gateway approach with α recycling to test the primary and secondary outcomes, allowing us to test each outcome at the full α = 0.05 level. The median and minimum/maximum (ie, range) pain scores by group at each time point are shown (Table 2).
A—Percentage of dogs that had a relatively elevated CSU-CAPS score (score ≥ 1) at each pain assessment time point after administration of either BUPIV or NOCI at the time of closure following performance of open ovariohysterectomy by a veterinary student in a surgical teaching laboratory. Dogs that received BUPIV were 65% more likely (P = .049) than those that received NOCI to experience elevated pain at some pain assessment time point after surgery. B—Percentage of dogs that had a relatively elevated the Glasgow Composite Measures Pain Scale–Short Form score (score 3) at each pain assessment time point after administration of either BUPIV or NOCI at the time of closure following performance of open ovariohysterectomy by a veterinary student in a surgical teaching laboratory. Dogs that received BUPIV were over twice as likely (P = .015) as those that received NOCI to have elevated pain at some pain assessment time point after surgery.
Citation: Journal of the American Veterinary Medical Association 261, 11; 10.2460/javma.23.01.0057
Pain scores (median, range) using the Colorado State University–Canine Acute Pain Scale (CSU-CAPS) and Glasgow Composite Measures Pain Scale–Short Form (GCPS-SF) by treatment group at each time point following administration of either BUPIV or NOCI for incisional analgesia after undergoing ovariohysterectomy in a veterinary teaching laboratory.
| Pain scale | Group | Time point (h) | Median | Minimum | Maximum |
|---|---|---|---|---|---|
| CSU-CAPS | NOCI (n = 71) | 0–4 | 0 | 0 | 2 |
| 4–8 | 0 | 0 | 3 | ||
| 8–12 | 0 | 0 | 3 | ||
| ≥ 12 | 0 | 0 | 1 | ||
| BUPIV (n = 65) | 0–4 | 0 | 0 | 3 | |
| 4–8 | 0 | 0 | 3 | ||
| 8–12 | 0 | 0 | 2 | ||
| ≥ 12 | 0 | 0 | 2 | ||
| GCPS-SF | NOCI (n = 71) | 0–4 | 1 | 0 | 9 |
| 4–8 | 1 | 0 | 10 | ||
| 8–12 | 0 | 0 | 10 | ||
| ≥ 12 | 0 | 0 | 8 | ||
| BUPIV (n = 65) | 0–4 | 2 | 0 | 9 | |
| 4–8 | 2 | 0 | 11 | ||
| 8–12 | 1 | 0 | 12 | ||
| ≥ 12 | 0 | 0 | 8 |
Discussion
In this study evaluating postoperative incisional analgesia for ovariohysterectomy in dogs, those that received an infiltrative block with liposomal bupivacaine were significantly less likely to require rescue analgesia administration than those that received a bupivacaine splash block. As well, there was an overall time-averaged significant difference between CSU-CAPS and GCPS-SF scores between groups, with those that received an infiltrative block with liposomal bupivacaine being less likely to have an elevated pain score. These findings supported our hypotheses that dogs in NOCI would require a lower incidence of rescue analgesia and dogs that received an infiltrative block with liposomal bupivacaine would have lower pain scores than those that received a splash block with bupivacaine.
It is worth noting that overall pain scores were low in both groups. Based on the skewed distribution of scores, a score of 3 on GCPS-SF and a score of 1 on CSU-CAPS were defined as the cutoff for being relatively elevated, while both of those numbers still fell below a score warranting treatment with rescue analgesia per the guidance of each scale. A previous study17 comparing the use of liposomal bupivacaine to traditional bupivacaine (both administered via a periarticular soft tissue injection) found a significant difference in rescue analgesia administration but not pain scores. This discrepancy could have occurred because the sensitivity of the assessment techniques was insufficient to detect a difference between groups and/or overall inadequate sensitivity to detect a painful animal. Another previous study7 evaluating incisional use of a local anesthetic failed to find a difference between a positive control (treatment with an opioid and a local anesthetic technique) and a negative control on 3 different pain scales, including a modified GCPS, similarly suggesting that these pain assessments could be insufficient to reliably identify pain in dogs. Therefore, perhaps scores in this study were low due to insufficient sensitivity to detect pain in this patient population. Additionally, the multimodal analgesic protocol used in this study might have resulted in lower overall pain scores. Despite this known limitation, it was not considered ethically appropriate to deny dogs in this laboratory the additional analgesic drugs that had been established as standard of care in this setting. Interestingly, the previously mentioned study evaluating the use of incisional liposomal bupivacaine in which no significant difference in pain scores was noted utilized a similar protocol that also included opioid and NSAID administration in addition to the local anesthetic treatment.17 The low overall pain scores found may also warrant consideration of whether the significant difference in pain scores found between groups was clinically relevant. However, as there was also a significant difference in whether rescue analgesia was administered, this would support that this difference in scores was clinically meaningful.
Another consideration regarding the validity of pain assessment in this study is that visceral pain may also occur with ovariohysterectomy.19 This would not be treated by incisional analgesia and could have influenced pain assessment. Visceral pain not treated by this local block could cause an increase in overall pain score, or it might be missed by an assessment that too heavily focuses on a surgical incision (ie, through evaluation of response to palpation of the surgical site). It is possible that a bupivacaine splash block on the linea alba after closure may lead to diffusion of local anesthetic into the peritoneal cavity and provision of some visceral analgesia. This would not be expected with liposomal bupivacaine. On the contrary, as liposomal bupivacaine is not expected to diffuse, it is more likely that dogs in NOCI may have received incomplete blocks if the liposomal bupivacaine was not effectively deposited along the entire length of the incision. The interplay of these factors could have confounded resulting analgesia and pain assessment. One could postulate that dogs may have been most painful immediately after surgery, especially as the NSAID was not administered until after extubation. A study8 evaluating incisional versus IP bupivacaine for analgesia for ovariohysterectomy found a difference in one of the pain assessments at 1 hour after the end of surgery but not at subsequent time points for the next 24 hours. This could have reflected easier discrimination of painful dogs using pain scoring (visual analog scale and numeric rating scale in this study) at that time, especially as that was the time point in that study at which the greatest number of doses of rescue analgesia were administered.8 Therefore, pain scores might have been expected to be higher and possibly more telling at the first time point in our study. However, this was not the time point in our study at which the greatest overall percentage of dogs were rescued. Dogs may also have been more likely to have had altered mentation from the residual effects of anesthetics immediately after extubation, which could have affected their pain score as a result, though dogs that were exhibiting excitement to the point of necessitating sedation were excluded from analysis. Ultimately, we believe whether the patients had adequate analgesia from their block as to not need rescue analgesia is more clinically relevant. Therefore, even though the validity of these pain scales in this context as well as more generally can be debated, we propose that these findings still support that the infiltrative block with liposomal bupivacaine offered a superior analgesic option.
The results of this study also indicated that there was a significant difference in time to administration of rescue analgesia between groups, as would be expected given the longer purported duration of liposomal bupivacaine (up to 72 hours) compared to traditional bupivacaine (range, 3 to 10 hours).2,30,31 However, dogs in NOCI that were rescued on average required analgesia much earlier than 72 hours, and the difference between groups in average time to rescue was not a clinically large one. Therefore, this finding might suggest that the results of this study should be taken more as an indication of a difference in efficacy of these 2 techniques only and not also in duration of efficacy. A review of postoperative pain with the use of liposomal bupivacaine infiltrated at the surgical site in humans discussed some studies that have not found superiority of liposomal bupivacaine over bupivacaine over 72 (or even 24) hours, though pain scores were lower with liposomal bupivacaine at an earlier time point (12 hours).32 It could also be that the effect of liposomal bupivacaine was not terminated earlier than expected in these dogs, rather it was still effective yet merely insufficient for pain control in those individual animals. This finding might especially be true when considering the potential contribution of visceral pain in these patients as previously discussed. Future studies might follow dogs for a longer period after ovariohysterectomy to better characterize the timing of need for rescue to further investigate this somewhat unexpected result.
This study had multiple limitations that warrant discussion. First, the pain scale (CSU-CAPS) used to dictate rescue analgesia administration is not a validated scoring scheme in dogs. It is, however, widely used clinically, and the validated scale (GCPS-SF) that was also used found a similar increase in elevated pain scores in the BUPIV group compared to the NOCI group. However, as the need for rescue analgesia was the primary outcome evaluated in this study, it is possible that alternatively using the validated GCPS-SF scale to determine whether rescue analgesia was needed could have influenced this outcome. Next, the original enrollment goal of 200 dogs on which the power analysis was based was not met. However, the study was still adequately powered, as a significant finding was found for the primary outcome of rescue analgesia requirement as well as the secondary outcome of pain scores. Another potential limitation was that the technique of drug administration and total dose and volume of drug administered differed between groups, but this difference was inherent in our design. Our study compared 2 techniques for incisional analgesia as much as it compared the drugs used, so we utilized the dose and volume of standard bupivacaine used previously in this laboratory and the label dose and volume for liposomal bupivacaine. Also, a larger volume of bupivacaine may be wasted in runoff from the incision as opposed to the larger volume of liposomal bupivacaine, which would not, due to it being infiltrated in the tissue layers rather than being splashed. Therefore, increasing the dose and/or volume of bupivacaine to match more closely that of liposomal bupivacaine might have been of limited effect and value. Moreover, the slow-release mechanism of liposomal bupivacaine allows for higher dosing than standard bupivacaine because lower peak concentrations in the blood are reached, so a higher dose of liposomal bupivacaine posed less of a risk of toxicity than if the bupivacaine dose was increased.31
Next, despite our best attempts at standardization, the study did include some unexpected protocol variations. However, these recognized variations resulted in exclusion from analysis in attempts to minimize confounding factors such as variability between evaluators and block administrators and potential impact on pain and pain assessment when additional surgical procedures were performed. As well, animals were excluded from analysis in attempts to minimize the potential influence of other drugs administered on pain assessment, as it has been suggested that maropitant, as a neurokinin-1 receptor antagonist, may have analgesic properties, even sedatives without analgesic properties may alter how a patient responds to pain assessment, and the omission of or discontinuation of an NSAID analgesic could impact pain level.33–36
Other potential sources of variability included some factors that could not be well controlled owing to this study being conducted within a teaching laboratory, in a diverse patient population, and over several months. First, dogs had different surgeons, though they were all novice veterinary students that were at the same point in their training. Second, as the exact start time and length of surgery varied, pain assessments at set hours did not occur at the same time from incisional block administration and end of surgery. Next, the length of surgery and anesthesia was different between groups, and a longer surgery could have meant more pain from greater tissue handling. As the mean surgery time was longer in NOCI, though, this would strengthen our conclusion of more effective analgesia being provided by this drug treatment, as incidence of rescue and pain scores were lower despite a longer surgery. As well, the authors would argue that a difference in average surgery time of only about 15 minutes would be unlikely to be clinically impactful even if it was statistically significant when average total surgery times were as long as they were in this surgical instruction setting. However, it should be noted that this longer surgical and anesthesia time could potentially be related to longer time needed to administer the infiltrative versus splash block, which may need to be taken into consideration when deciding whether to utilize this technique. Next, pain assessment did not always occur in a consistent, calm environment, as all dogs were housed in cages in the same room in which students would perform treatments to care for the animals throughout their stay, so the stimulation of the surrounding environment may have affected dogs’ performances on pain assessments. Finally, not all animals received the same NSAID, as their weight and drug availability limited what could be administered, though all drugs administered still worked via the same basic mechanism of action. Studies that have compared carprofen, meloxicam, and robenacoxib for their analgesic effects postoperatively in dogs have found these drugs to have similar efficacy, and individual dogs may have a variable response to a particular NSAID so that one drug should not be considered innately more effective than another.37–40
Results indicate the potential benefit of infiltrative administration of liposomal bupivacaine for abdominal incisional analgesia for spay surgery. Possible applications include dogs undergoing outpatient surgery or those housed in an animal shelter that commonly undergo ovariohysterectomy without constant monitoring by veterinary personnel postoperatively. On the basis of the findings of this study coupled with the authors’ experience with liposomal bupivacaine in other contexts, similar superiority of infiltration of this drug compared to splashing standard bupivacaine may be expected for incisional analgesia for other abdominal procedures. However, it is worth discussing whether the benefit demonstrated here (ie, a rescue proportion of 0.35 and time to rescue of 385 minutes for traditional bupivacaine compared to 0.2 and 425 minutes for liposomal bupivacaine) is sufficient to overcome the common barrier to using this liposomal bupivacaine more widely (in addition to limited label indications), which is its high cost compared to traditional bupivacaine.
In this study, the label recommendation was followed, and excess liposomal bupivacaine was considered waste if it had been > 4 hours after a vial had been punctured. However, a study41 evaluating the sterility of liposomal bupivacaine in a multidose fashion over a longer period suggested that, with sterile technique, it may be possible to use it up to 4 days. Also, the full dose (5.3 mg/kg) was used for each patient in this study. In high-quality, high-volume spay/neuter, incision size may be very small so that much smaller volumes would be necessary per patient. According to the liposomal bupivacaine label, smaller amounts can be diluted to a larger volume.31 Both a reduction in drug volume and an expansion of the time period of safe administration could reduce cost. The relative efficacy of administration of lower doses and/or diluted volumes of liposomal bupivacaine warrants further investigation, as this may be 1 way that the high cost of this medication could be ameliorated. As well, reevaluation of the use of liposomal bupivacaine in a similar experiment in which dogs undergoing abdominal surgery were evaluated for a greater amount of time after surgery might give insight as to any potential benefit of liposomal bupivacaine over traditional bupivacaine for longer lasting analgesia that would support its use despite the higher cost.
On a related note, the authors did not expect the overall relatively low incidence of rescue analgesia administration. Prior to this study, buprenorphine was administered every 6 hours for 24 hours postoperatively for every animal rather than utilizing pain score–directed rescue analgesia only. Although there are limitations to pain assessment that have been mentioned, this study supports that, in addition to potentially improving patient care by limiting unnecessary opioid administration (which can be associated with patient side effects and risk of diversion), postoperative pain assessment may offer an economic advantage.42,43 This approach could be of benefit in certain contexts, such as low-cost care clinics, when resources are limited and consideration must be made to allocate those resources to where they can be of greatest benefit. When making the decision to utilize liposomal bupivacaine, omission of unnecessary opioid administration through pain scoring and a locoregional technique would not be expected to outweigh the high price of this drug, but this spared cost may represent another way that the expense could be partially offset in addition to dose and volume reduction. However, the authors would still caution that pain scoring is not infallible, and it should not be inappropriately utilized as a means to simply cut costs at the risk of compromising patient welfare. Rather it should be considered as an adjunctive tool to maximize patient care.
The findings of this study support that the use of an infiltrative block with liposomal bupivacaine decreased the need for rescue analgesia compared to a bupivacaine splash block used for incisional analgesia in dogs undergoing ovariohysterectomy in a teaching laboratory. Liposomal bupivacaine administered in this manner may offer a superior analgesic option for dogs undergoing ovariohysterectomy or other abdominal or general surgical procedures. Further research is warranted to evaluate the efficacy and additional benefits of applications of this drug beyond this model and mode of administration as well as to further characterize the duration of analgesia expected when liposomal bupivacaine is employed in this manner.
Supplementary Materials
Supplementary materials are posted online at the journal website: avmajournals.avma.org
Acknowledgments
Funding for this study was provided by the Companion Animal Health Fund from the Cummings School of Veterinary Medicine, at Tufts University.
The authors would like to thank the staff of the Luke and Lily Spay and Neuter Clinic at the Cummings School of Veterinary Medicine at Tufts University who assisted in subject recruitment, local block administration, and the necessary function of the laboratory in which this study took place. The authors would also like to thank the Cummings School of Veterinary Medicine Class of 2021 who made up the students that were part of the laboratory course the year that data was collected for this study. Lastly, the authors would like to thank the substitute evaluator who performed pain assessment when the primary evaluator was unavailable.
References
- 1.↑
Epstein M, Rodan I, Griffenhagen G, et al. 2015 AAHA/AAFP pain management guidelines for dogs and cats. J Am Anim Hosp Assoc. 2015;51(2):67-84.
- 2.↑
Garcia E. Local anesthetics. In: Grimm KA, Lamont LA, Tranquilli WJ, Greene SA, Robertson SA, eds. Veterinary Anesthesia and Analgesia: The Fifth Edition of Lumb and Jones. 5th ed. Wiley Blackwell; 2015:332-354.
- 3.↑
Steagall PVM, Benito J, Monteiro B, et al. Intraperitoneal and incisional analgesia in small animals: simple, cost-effective techniques. J Small Anim Pract. 2020;61(1):19-23. doi:10.1111/jsap.13084
- 4.↑
Carpenter RE, Wilson DV, Evans AT. Evaluation of intraperitoneal and incisional lidocaine or bupivacaine for analgesia following ovariohysterectomy in the dog. Vet Anaesth Analg. 2004;31(1):46-52. doi:10.1111/j.1467-2995.2004.00137.x
- 5.↑
Wilson DV, Barnes KS, Hauptman JG. Pharmacokinetics of combined intraperitoneal and incisional lidocaine in the dog following ovariohysterectomy. J Vet Pharmacol Ther. 2004;27(2):105-109. doi:10.1111/j.1365-2885.2004.00552.x
- 6.↑
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):395-401. doi:10.2460/javma.237.4.395
- 7.↑
McKune CM, Pascoe PJ, Lascelles BD, Kass PH. The challenge of evaluating pain and a pre-incisional local anesthetic block. PeerJ. 2014;2:e341. doi:10.7717/peerj.341
- 8.↑
Campagnol D, Teixeira-Neto FJ, Monteiro ER, Restitutti F, Minto BW. Effect of intraperitoneal or incisional bupivacaine on pain and the analgesic requirement after ovariohysterectomy in dogs. Vet Anaesth Analg. 2012;39(4):426-430. doi:10.1111/j.1467-2995.2012.00728.x
- 9.↑
Kalchofner Guerrero KS, Campagna I, Bruhl-Day R, Hegamin-Younger C, Guerrero TG. Intraperitoneal bupivacaine with or without incisional bupivacaine for postoperative analgesia in dogs undergoing ovariohysterectomy. Vet Anaesth Analg. 2016;43(5):571-578. doi:10.1111/vaa.12348
- 10.↑
Kim YK, Lee SS, Suh EH, et al. Sprayed intraperitoneal bupivacaine reduces early postoperative pain behavior and biochemical stress response after laparoscopic ovariohysterectomy in dogs. Vet J. 2012;191(2):188-192. doi:10.1016/j.tvjl.2011.02.013
- 11.
Savvas I, Papazoglou LG, Kazakos G, Anagnostou T, Tsioli V, Raptopoulos D. Incisional block with bupivacaine for analgesia after celiotomy in dogs. J Am Anim Hosp Assoc. 2008;44(2):60-66. doi:10.5326/0440060
- 12.↑
Bubalo V, Moens YP, Holzmann A, Coppens P. Anaesthetic sparing effect of local anaesthesia of the ovarian pedicle during ovariohysterectomy in dogs. Vet Anaesth Analg. 2008;35(6):537-542. doi:10.1111/j.1467-2995.2008.00421.x
- 13.↑
Gruen ME, Lascelles BDX, Colleran E, et al. 2022 AAHA pain management guidelines for dogs and cats. J Am Anim Hosp Assoc. 2022;58(2):55-76. doi:10.5326/JAAHA-MS-7292
- 14.↑
Lascelles BDX, Kirkby Shaw K. An extended release local anaesthetic: potential for future use in veterinary surgical patients? Vet Med Sci. 2016;2(4):229-238. doi:10.1002/vms3.43
- 15.↑
EXPAREL: non-opioid analgesic pain management. Pacira Biosciences I. Accessed October 21, 2021. https://www.exparel.com/hcp/index
- 16.↑
Lascelles BD, Rausch-Derra LC, Wofford JA, Huebner M. Pilot, randomized, placebo-controlled clinical field study to evaluate the effectiveness of bupivacaine liposome injectable suspension for the provision of post-surgical analgesia in dogs undergoing stifle surgery. BMC Vet Res. 2016;12(1):168. doi:10.1186/s12917-016-0798-1
- 17.↑
Reader RC, McCarthy RJ, Schultz KL, et al. Comparison of liposomal bupivacaine and 0.5% bupivacaine hydrochloride for control of postoperative pain in dogs undergoing tibial plateau leveling osteotomy. J Am Vet Med Assoc. 2020;256(9):1011-1019. doi:10.2460/javma.256.9.1011
- 18.↑
Nocita for dogs. Elanco. Accessed March 21, 2021. https://www.elanco.us/products-services/dogs/nocita
- 19.↑
Gaynor JS, Muir WW. Acute pain management: a case-based approach. In: Gaynor JS, Muir WW, eds. Handbook of Veterinary Pain Management. 3rd ed. Elsevier; 2015:444-446. doi:10.1016/B978-0-323-08935-7.00022-3
- 20.↑
Hardie EM, Hansen BD, Carroll GS. Behavior after ovariohysterectomy in the dog: what’s normal? Appl Anim Behav Sci. 1997;51(1-2):111-128. doi:10.1016/S0168-1591(96)01078-7
- 21.↑
EXPAREL in obstetrics and gynecologic surgery. Exparel. Accessed March 21, 2021. https://www.exparel.com/hcp/specialty/obstetrics-and-gynecologic
- 22.↑
Reddi D, Curran N. Chronic pain after surgery: pathophysiology, risk factors and prevention. Postgrad Med J. 2014;90(1062):222-227. doi:10.1136/postgradmedj-2013-132215
- 23.↑
Ettinger SJ, Feldman EC, Côté E. The physical exam. In: Ettinger SJ, Feldman EC, Côté E, eds. Textbook of Veterinary Internal Medicine. 8th ed. Elsevier Inc; 2017:4-24.
- 24.↑
Reid J, Nolan AM, Hughes JML, Lascelles D, Pawson P, Scott EM. Development of the short-form Glasgow Composite Measure Pain Scale (CMPS-SF) and derivation of an analgesic intervention score. Anim Welf. 2007;16(S1):97-104. doi:10.1017/S096272860003178X
- 25.↑
Hellyer PW, Uhrig SR, Robinson NG. Colorado State University Canine Acute Pain Scale. Veterinary Anesthesia and Analgesia Support Group. Accessed April 4, 2021. https://www.vasg.org/pdfs/CSU_Acute_Pain_Scale_Canine.pdf
- 27.↑
Alosh M, Bretz F, Huque M. Advanced multiplicity adjustment methods in clinical trials. Stat Med. 2014;33(4):693-713. doi:10.1002/sim.5974
- 29.↑
Schulz KF, Altman DG, Moher D, Group C; CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c332. doi:10.1136/bmj.c332
- 30.↑
Lerche P, Aarnes T, Covey-Crump G, Martinez Taboada F. Introduction. Handbook of Small Animal Regional Anesthesia and Analgesia Techniques. Wiley Blackwell; 2016:1-12. doi:10.1002/9781119159490
- 32.↑
Hamilton TW, Athanassoglou V, Mellon S, et al. Liposomal bupivacaine infiltration at the surgical site for the management of postoperative pain. Cochrane Database Syst Rev. 2017;2(2):CD011419. doi:10.1002/14651858.CD011419.pub2
- 33.↑
Pang DSJ. Anesthetic and analgesic adjunctive drugs. In: Grimm KA, Lamont LA, Tranquilli WJ, Greene SA, Robertson SA, eds. Veterinary Anesthesia and Analgesia: The Fifth Edition of Lumb and Jones. 5th ed. Wiley Blackwell; 2015:244-259. doi:10.1002/9781119421375.ch13
- 34.
Marquez M, Boscan P, Weir H, Vogel P, Twedt DC. Comparison of NK-1 receptor antagonist (Maropitant) to morphine as a pre-anaesthetic agent for canine ovariohysterectomy. PLoS One. 2015;10(10):e0140734. doi:10.1371/journal.pone.0140734
- 35.
Boscan P, Monnet E, Mama K, Twedt DC, Congdon J, Steffey EP. Effect of maropitant, a neurokinin 1 receptor antagonist, on anesthetic requirements during noxious visceral stimulation of the ovary in dogs. Am J Vet Res. 2011;72(12):1576-1579. doi:10.2460/ajvr.72.12.1576
- 36.↑
Murrell JC. Pre-anesthetic medication and sedation. In: Duke-Novakovski T, Vries Md, Seymour C, eds. BSAVA Manual of Canine and Feline Anaesthesia and Analgesia. 3rd ed. British Small Animal Veterinary Association; 2016:170-189. doi:10.22233/9781910443231.13
- 37.↑
Laredo FG, Belda E, Murciano J, et al. Comparison of the analgesic effects of meloxicam and carprofen administered preoperatively to dogs undergoing orthopaedic surgery. Vet Rec. 2004;155(21):667-671. doi:10.1136/vr.155.21.667
- 38.
Gruet P, Seewald W, King JN. Evaluation of subcutaneous and oral administration of robenacoxib and meloxicam for the treatment of acute pain and inflammation associated with orthopedic surgery in dogs. Am J Vet Res. 2011;72(2):184-193. doi:10.2460/ajvr.72.2.184
- 39.
Gruet P, Seewald W, King JN. Robenacoxib versus meloxicam for the management of pain and inflammation associated with soft tissue surgery in dogs: a randomized, non-inferiority clinical trial. BMC Vet Res. 2013;9(92):92. doi:10.1186/1746-6148-9-92
- 40.↑
KuKanich B, Bidgood T, Knesl O. Clinical pharmacology of nonsteroidal anti-inflammatory drugs in dogs. Vet Anaesth Analg. 2012;39(1):69-90. doi:10.1111/j.1467-2995.2011.00675.x
- 41.↑
Carlson AR, Nixon E, Jacob ME, Messenger KM. Sterility and concentration of liposomal bupivacaine single-use vial when used in a multiple-dose manner. Vet Surg. 2020;49(4):772-777. doi:10.1111/vsu.13380
- 42.↑
The opioid epidemic: what veterinarians need to know. US FDA. Accessed April 2023. https://www.fda.gov/animal-veterinary/resources-you/opioid-epidemic-what-veterinarians-need-know
- 43.↑
KuKanich B, Wiese A. Opioids. In: Grimm KA, Lamont LA, Tranquilli WJ, Greene SA, Robertson SA, eds. Veterinary Anesthesia and Analgesia: The 5th edition of Lumb and Jones. John Wiley & Sons Inc.; 2015:207-226.
