Traditional perioperative pain management techniques for orthopedic surgery in dogs include epidural,1–3 intra-articular,4 loco-regional,5–7 and IV and oral8,9 administration of analgesic medications, alone or in combination.10 Opioids are the most effective drug class for the management of acute pain in small animals11 but may be associated with dysphoria,12,13 nausea, regurgitation, and vomiting.14 Additionally, the bioavailability of opioids after oral administration in dogs is poor,15 largely limiting the use of these drugs to hospital settings. Epidurally administered opioids have been shown to provide analgesia in dogs after TPLO while minimizing some of the adverse effects associated with systemic administration.1,2
Local anesthetics such as bupivacaine have been shown to treat pain associated with TPLO when provided by epidural administration1,3 or in the form of peripheral nerve blocks.5–7,16 Peripheral nerve blocks have similar efficacy to that found for epidural opioid administration for treatment of pain after TPLO,5,6 but with potentially fewer adverse effects.6 The clinical use of peripheral nerve blocks for this type of surgery is often limited because of the need for advanced training and specialized equipment.6,17 Incisional infiltration with local anesthetic is easier to perform, but this technique's effectiveness in decreasing postoperative analgesic requirements is unclear.18,19 To the authors’ knowledge, no study has shown the effectiveness of standard-formulation local anesthetics or epidurally administered opioids for treatment of pain in dogs longer than 24 hours after TPLO.
An extended-release liposomal formulation of bupivacaine is available that is intended to provide analgesia for up to 72 hours after cranial cruciate ligament surgery in dogs when administered by tissue infiltration.20 This product is marketed to provide continued analgesia for dogs after they have been discharged to the home environment and can no longer receive parenteral analgesics.20 Liposome-encapsulated bupivacaine has been available in human medicine since 2011, but results of studies21–23 evaluating its use as part of a multimodal pain management strategy in people have been mixed. There is a considerable cost difference between LEB and nonliposomal formulations of bupivacaine, and to the authors’ knowledge, no study in veterinary medicine has compared the effectiveness of LEB with that of other bupivacaine formulations for analgesia after surgery in dogs.
The objective of the study reported here was to compare analgesic effects of LEB and a nonliposomal formulation of 0.5BH injected into periarticular soft tissues of the affected stifle joint region after TPLO. Our hypotheses were that dogs receiving LEB would have less postoperative pain (as indicated by pain scale scores and a higher tolerance to incisional pressure), have a lower requirement for opioid administration (assessed by the proportion of dogs receiving opioids and the amounts of opioids administered), and would walk and eat earlier in the postoperative recovery period, compared with dogs receiving 0.5BH.
Materials and Methods
Animals
Client-owned dogs undergoing TPLO for treatment of cranial cruciate ligament rupture at the Tufts University Cummings School of Veterinary Medicine between August 10, 2017, and March 16, 2018, were eligible for study enrollment. Inclusion criteria were as follows: presence of a confirmed unilateral cranial cruciate ligament rupture, age ≤ 12 years, body weight from 20 to 80 kg (44 to 176 lb), body condition score from 2 to 7 (scale, 1 to 9),24 and general good health for anesthesia on the basis of physical examination, serum biochemical analysis, and CBC results. Dogs with a preexisting condition that precluded administration of an NSAID and dogs with a temperament that would make pain assessment difficult were excluded. The study was approved by the university's animal care and use committee. Informed owner consent was obtained prior to inclusion of dogs in the study.
Study design
Dogs were randomly assigneda to 2 treatment groups: LEBb (5.3 mg/kg [2.4 mg/lb]) or 0.5BHc (1.5 mg/kg [0.68 mg/lb]). Before surgery, dogs were premedicated with hydromorphone (0.1 mg/kg [0.05 mg/lb], IM) and acepromazine (0.01 to 0.05 mg/kg [0.005 to 0.023 mg/lb], IM; dose determined on the basis of age, breed, and temperament). A sterile 18 - to 22-gauge IV catheter was placed in the right or left cephalic vein. Anesthesia was induced with propofol (4 to 6 mg/kg [1.8 to 2.7 mg/lb], IV, to effect). Dogs were endotracheally intubated with an appropriately sized cuffed endotracheal tube and connected to a standard adult circle rebreathing circuit. Anesthesia was maintained by administration of isoflurane in oxygen. The standardized anesthesia protocol did not allow for epidural or peripheral nerve block techniques. During surgery, a balanced electrolyte solution was administered through a gravitational drip (5 mL/kg/h [2.3 mL/lb/h], IV) with lidocaine (50 μg/kg/min [22.7 μg/lb/min], IV) and ketamine (0.6 mg/kg/h [0.27 mg/lb/h], IV) included in the solution. If a dog's heart rate or systemic arterial blood pressure increased by > 20% of the baseline value (ie, the measurement obtained immediately after induction) for > 5 minutes, or if mean arterial blood pressure could not be maintained at ≥ 60 mm Hg with isoflurane as the maintenance anesthetic, a CRI of fentanyl (0.1 to 0.4 μg/kg/min [0.05 to 0.18 μg/lb/min], IV) was administered. If given, the CRI of fentanyl was discontinued at the time of subcutaneous tissue layer closure.
TPLO and study drug treatments
All TPLOs were performed by 1 board-certified surgeon (RJM). An arthrotomy was performed in all cases, and each component of the joint was evaluated. Torn components of the medial meniscus were excised if present. Intact menisci were left in situ.
After arthrotomy closure, osteotomy, and osteotomy stabilization,25 dogs were administered LEB or 0.5BH at the described doses in a manner similar to that indicated in the LEB technical monograph20: the assigned drug was injected slowly into the tissues through a 1.5-inch, 22-gauge needle by use of a moving needle technique, in which the needle was inserted to nearly the hub and the treatment was injected as the needle was withdrawn. Approximately 25%, 50%, and 25% of the assigned drug was injected into the tissues around the joint capsule, fascial tissue, and subcuticular tissue, respectively.20 Neither drug required dilution for administration, and the entire calculated dose of local anesthetic was administered in all cases. Following closure of the skin incision, all dogs underwent radiography to assess plate and screw placement.
Surgery time (measured from the time of first skin incision to final skin suture placement), total anesthesia time (measured from start of inhalation anesthetic delivery to the time it was discontinued), and time to extubation (measured from the end of inhalation anesthesia to time of removal of the endotracheal tube) were recorded for all dogs.
Postoperative monitoring, pain assessment, and treatments
At the time of extubation, dogs were administered carprofen (2.2 mg/kg [1 mg/lb], SC). Carprofen was administered SC at the same dose every 12 hours for the remainder of hospitalization. Dogs with signs of dysphoria at extubation received acepromazine (0.01 mg/kg, IV). Dogs were monitored for signs of pain by 2 investigators blinded to the treatment protocol (KLS and ARV) 0, 2, 4, 6, 8, 12, 16, 20, 24, 36, and 48 hours after surgery, with the time of extubation considered hour 0. Both investigators evaluated the first 10 study dogs independently, and duplicate pain scores were recorded for each dog. The duplicate pain scores were then analyzed for interobserver agreement, and the remainder of the study dogs were assessed by only 1 of the 2 investigators each time. Two pain scoring systems, the CSU-CAPS26 and the previously validated GCPS-SF27 were used to assess signs of pain for study purposes; however, the decision to provide rescue analgesia was made on the basis of CSU-CAPS pain scores.
For evaluation of signs of pain, dogs were observed from outside the cage, and assessments of body position, vocalization, and overall comfort were made. Investigators then observed whether the dog flinched, guarded, or vocalized in response to gentle palpation of the affected stifle region. Finally, investigators walked the dog outside the cage and evaluated the dog for signs of pain while walking, such as guarding the leg, vocalization, or reluctance to move. Behavioral signs (eg, general demeanor, vocalizations, attention to or guarding of the affected stifle region, and signs of interest in or responsiveness to surroundings or people), response to palpation of the affected region, and degree of body tension in awake dogs were recorded and scored on an overall scale of 0 (no signs of pain) to 4 (signs of moderate to severe pain) with the CSU-CAPS.26 Rescue analgesia (methadone, 0.1 mg/kg, IV) was provided for dogs that had a pain score ≥ 2 on this scale, which suggests mild to moderate pain and is the lowest score intended to trigger a reassessment of the analgesic plan.26 For the initial 10 dogs, if only 1 of the 2 observers assigned a score ≥ 2, the decision to provide rescue analgesia was made by the principal investigator (RCR), who was also blinded to the treatment protocol.
The GCPS-SF27 included 6 observational categories (vocalization in the kennel [scored from 0 to 3], attention to the affected stifle region [scored from 0 to 4], behavior on rising and walking [if able; scored from 0 to 4], response to palpation of the affected region [scored from 0 to 5], overall attitude including responsiveness to surroundings or stimulation [scored from 0 to 4], and signs of comfort or discomfort [scored from 0 to 4]). Higher scores indicated greater signs of pain, and the maximum total score was 24 for ambulatory dogs.27 This form was not used to make clinical decisions for rescue analgesia because of the influence that signs of anxiety and vocalization for reasons other than pain can contribute to the total score. Dogs that temporarily stopped vocalizing or ceased anxious behavior such as pacing or panting in response to attention from observers and were nonreactive to palpation of the affected stifle were considered anxious.
A spring-loaded PNT deviced was used at baseline (prior to premedication on the morning of surgery) and 2, 8, 24, and 48 hours after extubation to provide a more objective assessment of pain or discomfort at the surgery site than the pain scale scores. The device was used to gently apply pressure over the affected stifle joint by use of a 1-cm-diameter piston in a protocol similar to that reported previously.10 Briefly, the PNT device was placed perpendicular to the medial aspect of the affected stifle joint (over the joint space), and pressure was applied slowly at a constant rate until a maximum pressure of 4.5 kg/cm2 was reached or until the dog responded adversely by turning its head, vocalizing, or pulling its leg away from the device.10 The PNT measurements were recorded in kilograms per square centimeter according to the maximum pressure tolerated. A value of 4.5 kg/cm2 was recorded if no response to the PNT device was observed. Recorded values were converted to kilopascals for reporting purposes. This test was performed 2 hours after extubation to assess dogs during the early postoperative period, and it was repeated 8 hours after extubation to evaluate dogs as the anticipated duration of effect for the 0.5BH ended.28 Use of the PNT device 24 and 48 hours after extubation was intended to ensure that all dogs had the more objective pain measurement performed at least once every 24 hours throughout the postoperative hospitalization period.
Any dog that required a second dose of methadone for rescue analgesia on the basis of CSU-CAPS results was scheduled to regularly receive an opioid (methadone [0.1 mg/kg, IV, q 6 h] or hydromorphone [0.1 mg/kg, IV, q 4 h], depending on drug availability in the hospital) for analgesia until it could be transitioned to orally administered analgesics. Dogs that were scheduled for regular IV administration of opioid analgesics underwent pain scoring with the CSU-CAPS as scheduled to ensure adequate comfort, but the data were not used for study purposes owing to the confounding effect that these treatments would have on the results. These dogs were no longer assessed with the PNT device. The time to first administration of rescue analgesic and the total number of postoperative opioid doses were recorded when applicable. To account for differences in dosing frequency between methadone and hydromorphone, the total number of opioid doses administered was converted to MpE per kilogram of body weight for comparison with a previously described formula.29
All dogs were offered a small meal and walked outside (if they appeared willing and able) 4 hours after extubation. Dogs were then scheduled to be walked every 4 hours and fed every 8 to 12 hours until hospital discharge. The time to first walk and time to first meal (with the time of extubation considered hour 0) were recorded.
All dogs were monitored in the hospital for 48 hours after surgery and then discharged from the hospital with carprofen (2.2 mg/kg, PO, q 12 h). Forty-eight hours was the standard duration of hospitalization following TPLO. In an effort to minimize additional cost to dog owners for enrolling their dog in the study, owners (who were blinded as to the treatment group of dogs) were asked to complete a follow-up questionnaire at home to evaluate the status of dogs 72 hours after surgery. A visual analog scale for assessment of pain and lameness in dogs was modified from a previous study30 for this purpose. Briefly, owners were asked to rate the following variables on a scale of 1 (no pain; normal behavior) to 10 (worst pain imaginable; completely abnormal behavior) from the time of hospital discharge up to 72 hours after surgery: overall comfort level, overall attitude, frequency of postures indicating a happy dog, pain at rest, pain when rising, and pain when walking. A 10-cm visual analog scale was provided for each assessment, with contrasting descriptors at each end (eg, from no pain at all to worst pain imaginable or from normal behavior to completely abnormal behavior).30
Observer training for pain assessment
Observers were trained by the principal investigator (RCR) in postoperative pain assessment of dogs and use of the PNT device before the study began. Prior to the study, the principal investigator had considerable experience in pain scoring of hospitalized patients and in training of doctors and staff in postoperative pain assessment. Observer training in PNT device, CSU-CAPS, and GCPS-SF use included evaluation of hospitalized dogs concurrently with the principal investigator, who independently assessed signs of pain in each dog with the same methods during the training sessions. In-depth discussions regarding pain score determination were used to standardize how each category was assessed by the observers.
Statistical analysis
All statistical analyses were performed with commercially available software.e,f Age, sex, weight, surgery time, anesthesia time, and time from the end of surgery to extubation were assessed for normality by use of the Shapiro-Wilk test. Normally distributed data are presented as mean ± SD; nonnormally distributed data are presented as median and range. A Student t test was used to assess the difference in means between treatment groups for normally distributed data. A nonparametric Kruskal-Wallis χ2 test was used to compare variables that were not normally distributed. Agreement between observers for duplicate pain scores was tested by calculation of the Cohen κ statistic. Interobserver agreement was rated as none (0 to 0.20), minimal (0.21 to 0.39), weak (0.40 to 0.59), moderate (0.60 to 0.79), strong (0.80 to 0.90), and almost perfect (> 0.90).31 Pain scores were compared between treatment groups with a likelihood ratio χ2 test for the CSU-CAPS and a nonparametric Wilcoxon rank sum test for the GCPS-SF. A likelihood ratio χ2 test was used to compare the number of dogs in each treatment group that required treatment of dysphoria (with acepromazine) and rescue analgesia (with methadone). Kaplan-Meier product limit estimates with a log-rank statistical test were used to compare time to first administration of rescue analgesic, time to the first walk, and time to consuming the first meal after extubation between the 2 treatment groups. Nonparametric Wilcoxon rank sum tests were used to compare the total number of opioid doses and the total number of MpE between the 2 groups. A mixed-effects regression model was used to compare PNT measurements between the groups; time (number of hours) after extubation and treatment group were considered fixed effects, and individual dogs were considered as random effects. Values of P < 0.05 were considered significant in all analyses.
Results
Thirty-three client-owned dogs were initially enrolled in the study, and 28 dogs completed the study. Five dogs were removed from the study because of clinical events that were determined to potentially influence postoperative pain. One dog had intraoperative bleeding necessitating greater tissue dissection than typically performed, 1 dog had a fracture of the fibula during rotation of the tibial plateau segment, 1 dog had histiocytic sarcoma in the affected stifle region, 1 dog was not administered NSAIDs because of regurgitation during anesthesia, and 1 dog was returned to the operating room for correction of improper screw placement after the TPLO.
The 28 dogs that completed the study were divided equally between the LEB and 0.5BH groups. Eighteen were spayed females, and 10 were castrated males. Median age was 6.1 years (range, 0.8 to 11 years), and median body weight was 32.8 kg (72.2 lb; range, 24 to 72 kg [52.8 to 158.4 lb]). There were no significant intergroup differences in age (5.8 [LEB group] vs 6.2 [0.5BH group] years; P = 0.59), body weight (33.5 kg [73.7 lb; LEB group] vs 32.8 kg [0.5BH group]; P = 0.71), or sex (3 males and 11 females in the LEB group vs 7 and 7, respectively, in the 0.5BH group; P = 0.11).
Mean surgery time was 55.8 ± 8.1 minutes and 52.8 ± 10.1 minutes for the LEB and 0.5BH groups, respectively (P = 0.39). Mean anesthesia time was 130.3 ± 11.1 minutes for the LEB and 123.9 ± 14.4 minutes for the 0.5BH group (P = 0.20). Median time to extubation was 10 minutes (range, 7 to 15 minutes) and 14 minutes (range, 11 to 24 minutes) for the LEB and 0.5BH groups, respectively (P = 0.08). No dogs enrolled in the study required an intraoperative CRI of fentanyl on the basis of the described criteria. Three of 14 dogs in the LEB group and 2 of 14 dogs in the 0.5BH group required acepromazine at extubation (P > 0.99).
Agreement between pain scores assigned by the 2 trained observers was moderate for CSU-CAPS (κ = 0.67) and minimal for GCPS-SF (κ = 0.38) scores. During duplicate pain score assessments, there were no instances when only 1 of the 2 trained observers assigned a pain score of ≥ 2, and evaluation by the principal investigator was not needed. Postoperative pain scores as assessed with the CSU-CAPS and GCPS-SF during hospitalization were compared between treatment groups (Tables 1 and 2). There were no significant differences in pain scores between treatment groups at any time point by either scoring method. Three of 14 dogs that received LEB were assigned a CSU-CAPS score ≥ 2; 2 of these dogs were assigned a score ≥ 2 at least twice and were subsequently administered regular opioid treatments. Ten of 14 dogs that received 0.5BH were assigned a CSU-CAPS score ≥ 2, and all 10 of these dogs received such scores at least twice and were subsequently administered regular opioid treatments.
Median (range) postoperative pain scores as assessed by use of the CSU-CAPS26 for 28 dogs that received LEB (5.3 mg/kg [2.4 mg/lb]; n = 14) or 0.5BH (1.5 mg/kg [0.68 mg/lb]; 14) by local injection into periarticular soft tissues of the affected stifle joint after arthrotomy closure, osteotomy, and osteotomy stabilization during TPLO.
| LEB | 0.5BH | ||||
|---|---|---|---|---|---|
| Time after extubation (h) | Pain score | No. of dogs | Pain score | No. of dogs | P value |
| 0 | 0 (0-1.0) | 14 | 0 (0-1.0) | 14 | 0.554 |
| 2 | 0.5 (0-0.5) | 14 | 0.5 (0-2.5) | 14 | 0.595 |
| 4 | 0.5 (0-1.0) | 14 | 0.5 (0-2.0) | 14 | 0.069 |
| 6 | 0.5 (0-1.0) | 14 | 0.5 (1.0-2.0) | 13 | 0.420 |
| 8 | 0.5 (0.5-2.0) | 14 | 1.0 (0-2.0) | 13 | 0.351 |
| 12 | 0.5 (0-2.0) | 14 | 0.5 (0-2.0) | 11 | 0.563 |
| 16 | 0.5 (0.5-2.0) | 13 | 0.5 (0-2.0) | 9 | 0.515 |
| 20 | 0.5 (0-1.0) | 12 | 0.5 (0-2.0) | 6 | 0.127 |
| 24 | 0.5 (0-0.5) | 12 | 0.5 (0-1.5) | 5 | 0.514 |
| 36 | 0.5 (0-1.0) | 12 | 0.5 (0-0.5) | 4 | 0.147 |
| 48 | 0.5 (0-1.0) | 12 | 0 (0-0.5) | 4 | 0.801 |
All dogs received carprofen (2.2 mg/kg [1 mg/lb], SC, q 12 h) after surgery. Pain scores were assessed at the indicated time points, with the time of extubation considered hour 0, on an ordinal scale of 0 (no signs of pain) to 4 (signs of moderate to severe pain). A score ≥ 2 (signs of mild to moderate pain) was cause for rescue analgesia (methadone [0.1 mg/kg {0.05 mg/lb}], IV); dogs that required administration of the rescue analgesic more than once were scheduled to regularly receive an opioid treatment (methadone or hydromorphone) IV until they could be transitioned to orally administered analgesics, and all subsequent pain scoring data for these dogs were excluded from the analysis. Values of P < 0.05 were considered significant.
Median (range) postoperative pain scores as assessed by use of the GCPS-SF27 for the 28 dogs in Table 1.
| LEB | 0.5BH | ||||
|---|---|---|---|---|---|
| Time after extubation (h) | Pain score | No. of dogs | Pain score | No. of dogs | P value |
| 0 | 1.0 (0-5.0) | 14 | 1.0 (0-5.0) | 14 | 0.515 |
| 2 | 2.0 (1.0-6.0) | 14 | 2.5 (1.0-11.0) | 14 | 0.127 |
| 4 | 2.0 (1.0-6.0) | 14 | 2.0 (1.0-12.0) | 14 | 0.514 |
| 6 | 2.0 (1.0-5.0) | 14 | 3.0 (1.0-6.0) | 13 | 0.147 |
| 8 | 2.0 (1.0-8.0) | 14 | 3.0 (1.0-6.0) | 13 | 0.801 |
| 12 | 2.0 (1.0-5.0) | 14 | 3.0 (1.0-7.0) | 11 | 0.554 |
| 16 | 2.0 (1.0-6.0) | 13 | 2.0 (1.0-6.0) | 9 | 0.595 |
| 20 | 2.0 (1.0-4.0) | 12 | 1.5 (1.0-4.0) | 6 | 0.069 |
| 24 | 2.0 (1.0-3.0) | 12 | 2.0 (1.0-4.0) | 5 | 0.420 |
| 36 | 1.5 (1.0-3.0) | 12 | 2.0 (1.0-2.0) | 4 | 0.351 |
| 48 | 1.0 (1.0-3.0) | 12 | 1.0 (1.0-2.0) | 4 | 0.563 |
Pain scores reflect the sum of scores for 6 observational categories with associated descriptions, where 0 and 24 were the minimum and maximum sums of possible scores, respectively.27 The GCPS-SF scores were not used for determination of rescue analgesia requirements.
See Table 1 for remainder of key.
Baseline PNTs ranged from 264.8 to 441.3 kPa and from 323.6 to 441.3 kPa in the LEB and 0.5BH groups, respectively (Table 3). One dog in the LEB treatment group had an aggressive reaction to the PNT device at hour 24 but was not determined to have signs of pain. As a safety precaution, the PNT testing was not performed for this dog at hour 48. At the end of the study, the PNTs ranged from 88.3 to 441.3 kPa for the LEB group and from 166.7 to 284.4 kPa for the 0.5BH group. There were no significant differences in PNT values between treatment groups at any of the evaluated time points.
Median (range) PNT measurements over time for the 28 dogs in Table 1.
| LEB | 0.5BH | ||||||
|---|---|---|---|---|---|---|---|
| Time | PNT (kg/cm2) | PNT (kPa) | No. of dogs | PNT (kg/cm2) | PNT (kPa) | No. of dogs | P value |
| Baseline | 4.1 (2.7-4.5) | 402.1 (264.8-441.3) | 14 | 4.1 (3.3-4.5) | 402.1 (323.6-441.3) | 14 | 0.46 |
| Time after extubation (h) | |||||||
| 2 | 3.3 (1.5-1.5)* | 323.6 (147.1-441.3) | 14 | 2.6 (0.2-4.5)* | 255.0 (19.6-441.3) | 14 | 0.34 |
| 8 | 2.7 (1.4-1.5)* | 264.8 (137.3-441.3) | 14 | 1.7 (0.0-3.3)* | 166.7 (0.0-323.6) | 12 | 0.06 |
| 24 | 2.4 (1.0-4.5)* | 235.4 (98.1-441.3) | 12 | 2.1 (1.4-2.3)* | 206.0 (137.3-225.6) | 5 | 0.32 |
| 48 | 1.8 (0.9-4.5)* | 176.5 (88.3-441.3) | 11 | 2.3 (1.7-2.9)* | 225.6 (166.7-284.4) | 4 | 0.76 |
Testing with the PNT device was discontinued for dogs that required rescue analgesia more than once. One dog in the LEB group had an extremely aggressive reaction to the algometer at hour 24 but was not determined to have signs of pain. As a safety precaution, the PNT device was not used on this dog at hour 48. The P values represent comparisons between groups for a given time point.
Within a group, measurement is significantly (P < 0.001) lower than that at baseline (ie, prior to premedication on the morning of surgery).
See Table 1 for remainder of key.
Dogs in the LEB treatment group were significantly (P = 0.007) less likely to require rescue analgesia than dogs in the 0.5BH treatment group (3/14 and 10/14, respectively). The number of total opioid doses was significantly (P = 0.006) lower for the LEB group (median, 0) than for the 0.5BH group (median, 5.5; Figure 1). When adjusted to account for the differences in dosing frequency between methadone and hydromorphone, the total amount of opioids administered was also significantly (P = 0.005) lower for the LEB group (median, 0 MpE/kg) than for the 0.5BH group (median, 0.6 MpE/kg).
Box-and-whisker plots depicting the total number of opioid doses for 28 dogs that received LEB (5.3 mg/kg [2.4 mg/lb]; n = 14; dark gray boxes) or 0.5BH (1.5 mg/kg [0.68 mg/lb]; 14; light gray boxes) by local injection into periarticular soft tissues of the affected stifle joint after arthrotomy closure, osteotomy, and osteotomy stabilization during TPLO and the calculated total amount of opioids administered after adjustment for differences in dosing frequency between methadone and hydromorphone (MpEs per kilogram of body weight29). Dogs were evaluated for signs of pain at predetermined time points; a score ≥ 2 (signs of mild to moderate pain) on an ordinal scale of 0 (no signs of pain) to 4 (signs of moderate to severe pain) by use of the CSU-CAPS26 was cause for rescue analgesia (methadone [0.1 mg/kg {0.05 mg/lb}], IV). Not all dogs required rescue analgesia (n = 3 and 10 for LEB and 0.5BH groups, respectively); dogs that required a second dose of methadone were scheduled to receive regular opioid treatment (methadone [0.1 mg/kg, IV, q 6 h] or hydromorphone [0.1 mg/kg, IV, q 4 h], depending on drug availability in the hospital) until they could be transitioned to orally administered analgesics. One outlier in the 0.5BH group (40 MpE/kg [18.2 MpE/lb]) was removed from graphical representation for visual clarity but was included in all statistical analyses. Boxes indicate the interquartile (25th to 75th percentile) range, whiskers indicate the absolute range of values, horizontal bars within boxes represent the median, and diamonds represent the mean for each group. *The number of MpEs per kilogram is significantly (P = 0.005) less for the LEB group than for the 0.5BH group. †The number of opioid doses is significantly (P = 0.006) less for the LEB group than for the 0.5BH group.
Citation: Journal of the American Veterinary Medical Association 256, 9; 10.2460/javma.256.9.1011
Time to first administration of rescue analgesic, time to first walk, and time to consumption of the first meal after extubation were compared between treatment groups (Figure 2). Most dogs in the LEB (11/14) and 0.5BH groups (11/14) consumed their first meal ≤ 8 hours after surgery. Results were similar for having the first walk outside (12/14 and 14/14 for the LEB and 0.5BH groups, respectively). The 3 dogs in the LEB group that required rescue analgesia were first identified as having a CSU-CAPS pain score ≥ 2 at the 8-hour (n = 2) and 16-hour (1) time points after extubation. Seven of the 10 dogs in the 0.5BH group that required rescue analgesia were first identified as having these signs between 6 (n = 4) and 8 (3) hours after extubation. There was no significant difference in the measured times between groups for any of the 3 variables. All dogs were discharged from the hospital without further complications. Owner response rate to the follow-up questionnaire was low, and the results were not included in statistical analysis.
Box-and-whisker plots depicting time to first administration of rescue analgesic, time to first walk, and time to consumption of the first meal for 28 dogs that received LEB (5.3 mg/kg; n =14; dark gray boxes) or 0.5BH (1.5 mg/kg; 14; light gray boxes) by local injection into periarticular soft tissues of the affected stifle joint after arthrotomy closure, osteotomy, and osteotomy stabilization during TPLO. The time of extubation was considered hour 0. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 256, 9; 10.2460/javma.256.9.1011
Discussion
Results of the present study revealed that after TPLO, dogs that received LEB (5.3 mg/kg) by local tissue infiltration were significantly less likely to require rescue analgesia with an opioid than dogs administered 0.5BH (1.5 mg/kg) in the same manner. Three of 14 dogs administered LEB required rescue analgesia at least once prior to discharge from the hospital, compared with 10 of 14 dogs administered 0.5BH. These results were likely attributable to the differing durations of effect between the drugs. In dogs, bupivacaine has a reported therapeutic effect for 3 to 15 hours, depending on the method of administration and means of assessing analgesia.28,32 In contrast, LEB administered in accordance with the label is reported to have a duration of action of up to 72 hours.20
In our study, 7 of 14 dogs in the 0.5BH group required rescue analgesia between 6 and 8 hours after surgery (measured from the time of extubation). These results were similar to findings in a study6 performed to investigate the use of bupivacaine for femoral and sciatic nerve blocks in dogs undergoing TPLO. In that study,6 the mean time to first rescue analgesia was slightly longer, at 14 hours, than in the present study,6 likely as a result of the different administration methods used. Dogs that received 0.5BH in the present study were identified as having signs of mild to moderate pain (CSU-CAPS score ≥ 2/4) as analgesia provided by periarticular tissue injection with 0.5BH presumably ceased to be effective. Once this observation was made, all dogs in the 0.5BH treatment group required ≥ 2 IV doses of opioids.
In contrast, administration of LEB eliminated the need for IV opioid administration in most dogs in our study. The liposomes in LEB contain a phospholipid bilayer encapsulating an aqueous core, and these break down as the external phospholipid bilayer erodes slowly over time, allowing for its extended duration of effect.33 The 3 dogs in the LEB group that required rescue analgesia were identified as meeting rescue analgesia criteria 8 (n = 2) and 16 (1) hours after surgery. These results were consistent with results of another study17 that found LEB to provide sufficient analgesia (as assessed by the GCPS-SF) in 19 of 24 (79.2%) dogs during the first 24 hours after lateral retinacular suture placement. Dogs in the present study underwent TPLO and may have had bone pain that was not addressed by tissue infiltration with local anesthetic. However, no additional dogs in the LEB group had pain scores ≥ 2 with the CSU-CAPS after the 16-hour time point. This was in contrast to results of the previous study,17 in which the number of dogs considered to remain comfortable with LEB alone decreased to 10 of 24 (42%) by 48 hours after surgery. All dogs in the present study received carprofen in addition to LEB or 0.5BH, and it is possible that the combination of LEB and an NSAID contributed to improved analgesia over a longer duration of time. Possible causes of insufficient analgesia in some dogs administered LEB in the present study included premature breakdown of the liposomes, inconsistent infiltration of the drug during surgical closure, and individual variations in pain response.
Most dogs in both treatment groups ate a small meal and walked outside ≤ 8 hours after surgery. There was no significant difference in the time to first meal consumption or first walk between treatment groups, which might have been because the duration of the therapeutic effect of the nonliposomal formulation of bupivacaine is typically between 6 and 8 hours.28 This underscores the effectiveness of local anesthetics in supporting early mobilization and return to normal function in the immediate postoperative period.34 Ability to eat, walk, and have signs of pain managed with oral medications are common criteria for veterinary patients to be discharged from the hospital. All dogs in the present study remained in the hospital for 48 hours for observation and pain assessment, but most dogs in the LEB treatment group would have met these criteria for discharge from the hospital 24 hours after surgery. On the basis of the fee structure at the institution where the study took place, this difference in length of hospitalization would have resulted in the costs for both treatment groups remaining essentially the same. While the initial cost of LEB was greater than that of 0.5BH, a potential benefit of LEB is decreased hospitalization time without an increase in total cost of the procedure.
The results of the study reported here did not confirm our hypothesis that administration of LEB would result in lower pain scores, compared with administration of 0.5BH, but significantly fewer dogs in the LEB group had pain scores that reflected a need for rescue analgesia. As a clinical study, a goal of the design was to maintain appropriate postoperative comfort levels for all dogs. Once dogs were administered 2 doses of the rescue analgesic, their pain scores were no longer included in the statistical analysis and they received IV opioid administrations until deemed comfortable with oral pain medication alone by the attending clinicians. As a result, during the study period, most CSU-CAPS scores in both treatment groups were kept within tight ranges of 0 to 1 of 4, and this was unlikely to result in a statistically significant or clinically relevant difference.
Pain can be difficult to measure in dogs as it relies on behavioral observations and subjective interpretation of reactions to palpation. The CSU-CAPS is believed to be a useful assessment tool but has not undergone validation for clinical use.11 The GCPS-SF has been validated27,35; however, in prior clinical experience of 2 of the authors (RCR and ALA), dogs considered to be anxious received higher scores on the GCPS-SF, which triggered unnecessary administration of rescue analgesia for patients that did not have other evidence of pain warranting such treatment. Both pain scales were used concurrently in the present study, but because of these concerns, the protocol was designed so that clinical decisions were made on the basis of CSU-CAPS scores. Subjective assessment of individual data points showed that several dogs in both treatment groups scored above the traditional GCPS-SF treatment threshold (≥ 6/24)27 but were not considered to have signs of pain by the trained observers.
Use of the PNT device was intended to provide a more objective means of pain assessment36 in our study than the pain scale data. Surprisingly, there was no significant difference in PNT measurements between treatment groups at any time point, although the lowest measurements were found for dogs in the 0.5BH group 8 hours after surgery, and the median value for this group (166.7 kPa) appeared substantially lower than that for the LEB group at this time point (264.8 kPa). The timing of these measurements corresponded with the finding that most dogs in the 0.5BH treatment group that required rescue analgesia had this determination made 6 to 8 hours after surgery. Factors that may affect PNT scores include piston diameter, position of the dog when tested, and anatomic site used for testing.37 A uniform piston size was used for PNT measurements in the present study, but there were no restrictions on position of the dog while the PNT device was applied. Additionally, investigators of a previous study37 noted that mechanical threshold measurements obtained over the stifle region are more likely to result in unmeasurable values because of dogs’ avoidance behavior or slippage of the device. Most importantly, results of the previous study37 also indicated that individual variation among dogs (eg, temperament) had the greatest effect on response to this type of testing. Investigators of another study38 also noted that some dogs learned to recognize the PNT device and anticipate the stimulus, which may have resulted in inaccurate PNT scores (owing to earlier reactions) over time. Learned behavior in response to the PNT device was observed in at least 1 dog in the present study, as this dog became aggressive when the PNT device was visible. This dog was determined to be nonpainful when assessed for signs of pain by other methods at the same time point. Finally, the interval between postoperative PNT assessments in our study increased from 6 to 16 and finally 24 hours as the study went on, and differences between treatment groups may have been missed as a result. All of these factors might have contributed to inability to confirm the subjectively assessed differences between groups with the device measurements.
Another limitation of the present study was that dogs were evaluated for only 48 hours after TPLO. As part of the original study design, owners received a follow-up questionnaire to be completed 72 hours after surgery (the duration of analgesia anticipated for the LEB treatment),20 providing an assessment of the dog's comfort level by use of a visual analog scale. Very few owners completed the survey, and responses that were received did not follow the requested format to allow for statistical analysis. However, none of the dog owners contacted the hospital with concerns over inability to manage pain at home after the animal was discharged.
Another possible limitation of our study was that 2 observers assessed a subset of the dogs for pain scoring after surgery. However, both observers were trained by the principal investigator in postoperative pain assessment with both of the pain scales used prior to the start of the study. The principal investigator had considerable experience in pain scoring of hospitalized dogs as well as training doctors and staff in postoperative pain assessment. In-depth discussions among these investigators regarding how dogs were scored helped to standardize the way that each category was assessed. Additionally, analysis of interobserver agreement indicated that duplicate scores assigned by the 2 observers with the CSU-CAPS, which was used to assess the need for additional treatment, were in moderate agreement.
In addition, there was no control in the form of systemic opioid administration without local analgesic administration (or a local sham treatment) in this study. As a result, it was not possible to quantify any perceived reduction in opioid requirements with either of the treatments studied. Comparison with such a control group could have helped further elucidate whether local anesthetic protocols were of benefit in terms of early return to eating and walking following surgery.
In the study reported here, fewer dogs that received LEB by periarticular injection required rescue analgesia, compared with dogs that received 0.5BH by the same method, and dogs in the former group received a significantly lower total amount of opioids (MpEs) per kilogram of body weight in the first 48 hours after surgery, compared with the latter group. The LEB appeared to provide adequate analgesia after TPLO and could potentially minimize the need for opioid treatments, thus reducing the frequency of opioid-associated adverse effects and possibly allowing dogs to be discharged from the hospital earlier than is possible with traditional pain management strategies.
Acknowledgments
No third-party funding or support was received in connection with this study or the writing or publication of the manuscript. The authors declare that there were no conflicts of interest.
ABBREVIATIONS
| 0.5BH | 0.5% bupivacaine hydrochloride |
| CRI | Constant rate infusion |
| CSU-CAPS | Colorado State University-Canine Acute Pain Scale |
| GCPS-SF | Glasgow Composite Pain Scale-Short Form |
| LEB | Liposome-encapsulated bupivacaine |
| MpE | Morphine equivalents |
| PNT | Pressure nociceptive threshold |
| TPLO | Tibial plateau leveling osteotomy |
Footnotes
Randomization Plans. Available at: gdallal.pages.tufts.edu/assign.htm. Accessed Oct 10, 2019.
Nocita, Aratana Therapeutics, Leawood, Kan.
Sensorcaine - MPF, Fresenius Kabi USA, Lake Zurich, Ill.
Pain Test FPK/FPN, Wagner Instruments, Riverside, Conn.
R, version 3.1, R Foundation for Statistical Computing, Vienna, Austria. Available at: www.r-project.org. Accessed Mar 18, 2020.
SAS, version 9.4, SAS Institute, Inc, Cary, NC.
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