Abstract
Objectives
The objective of this study was to evaluate the impact of liposomal bupivacaine (LB) as part of an opioid-sparing multimodal analgesic protocol on postoperative pain control in cats undergoing limb amputation surgery compared with traditional pain management protocols more heavily reliant on injectable opioid and non-opioid analgesics.
Methods
Medical records of 29 cats that underwent forelimb or hindlimb amputation were reviewed to evaluate postoperative systemic pain medications utilized, appetite and time to discharge as presumptive gauges of postoperative pain. Statistical analysis of the data included Wilcoxon’s rank-sum test and Fisher’s exact test.
Results
Of the 29 cats, seven (24%) did not receive LB and 22 (76%) did. No statistically significant differences were found between the two groups in the outcome variables evaluated. The median time to eating was similar (6.0 h in the LB group vs 5.0 h in the non-LB group), the median time to discharge was shorter in the LB group (25.0 h vs 42.0 h in the non-LB group) and the median time to discontinuation of opioids in the LB treatment group was shorter than the non-LB group (18.0 h in LB group vs 22.0 h non-LB). A lower proportion of the LB group needed adjuvant systemic analgesics compared with the non-LB group (5% LB vs 29% non-LB).
Conclusions and relevance
The addition of liposomal bupivacaine to an analgesic protocol after limb amputation in cats is associated with reduced opioid dosing, earlier return to eating and earlier hospital discharge. The use of LB may minimize the negative side effects associated with systemic opioid administration and therefore decrease patient morbidity. Future studies are needed to definitively compare LB efficacy and safety for postoperative pain control and traditional systemic analgesic medications.
Introduction
There is a significant gap in the current veterinary literature regarding multimodal analgesic techniques in cats. A study conducted in 2010 evaluated owners’ assessments of their cats’ pain after discharge from hospital after limb amputation. Although 89% of cats received analgesics or anti-inflammatory medications for at-home use, 35% of owners still reported behavioral changes they interpreted as secondary to uncontrolled postoperative pain. 1
Despite recent advancements in pain recognition in cats,2,3 true postoperative pain can be difficult to differentiate from non-painful stress. Consequently, veterinary clinical practice has tended to rely heavily on the generalized administration of systemic analgesics, such as opioid medications, as standard management of acute surgical pain. However, there are well-documented risks associated with the use of systemic opioids, including dysphoria, regurgitation, vomiting and inappetence due to appetite suppression, nausea and/or ileus. 4 These systemic adverse effects related to opioid use have been well described in both humans and small animal veterinary patients. In cats, opioid-induced hyperthermia has also been reported and necessitates close monitoring of body temperature after opioid administration, although the clinical impact of this phenomenon is not yet fully understood. 5 Alternative systemic analgesics, such as non-steroidal anti-inflammatory drugs (NSAIDs), can be used in the postoperative period to minimize opioid use and thereby limit opioid-related adverse effects. 6 However, side effects related to NSAID usage in cats, such as gastrointestinal upset/ulceration and nephrotoxicity, 7 have also been documented and its usage may be contraindicated in cats with certain pre-existing comorbidities, such as chronic kidney disease and protein-losing enteropathies. 6 Local anesthesia is an effective opioid-sparing alternative method to prevent both transduction and transmission of nociceptive signaling. Although in recent years the usage of local anesthetics has become more popular in veterinary medicine, it has been historically under-utilized as a result of the technical skill required for local block administration and the short duration of the effect of local anesthetics. 8 In human medicine, a series of procedure-specific multimodal analgesic protocols utilizing local anesthetics in addition to other non-opioid analgesics have been developed by the Enhanced Recovery After Surgery (ERAS) Society to improve postoperative patient care. A key component of these protocols is the use of local anesthetics, as they have been consistently shown to decrease postoperative pain, overall opioid usage, postoperative hospitalization and long-term pain. With the ongoing global opioid crisis 9 and production delays of synthetic opioids, 10 this approach may be prudent to consider in veterinary medicine. While similar protocols have not yet been widely adopted in the veterinary setting, interest in the benefit of multimodal analgesia for overall patient wellbeing is increasing.
Emerging techniques in local long-acting anesthetics have become popular as a means to provide better long-term relief in postoperative patients. Liposomal bupivacaine (LB) (Nocita; Elanco) shows promise in veterinary medicine as an adjuvant anesthetic to provide consistent and long-lasting pain relief, although literature proving its efficacy remains limited in veterinary medicine.4,11 LB has become a common addition to the pain management of many surgical procedures as part of a multimodal postoperative pain management protocol. In human medicine, studies have shown that administration of LB results in a decreased need for systemic rescue analgesics,12,13 as well as reduced systemic side effects compared with traditional systemic analgesics, with no adverse effects on wound healing rate. 14 To date, LB efficacy has only been evaluated for cats undergoing onychectomy, 11 cats and dogs undergoing ovariohysterectomy15,16 and dogs undergoing tibial plateau leveling osteotomy procedures.4,11 In these studies, LB was found to be a well-tolerated and effective adjuvant anesthetic utilized as part of an opioid-sparing multimodal analgesic protocol for the previously mentioned surgical procedures that provided adequate postoperative analgesia while decreasing the need for rescue opioids. LB is frequently used off-label for a variety of different surgical procedures in both cats and dogs as there are no known contraindications for use; 17 however, further studies are required to demonstrate its efficacy for additional surgical procedures.
Limb amputations are a common surgical procedure performed in veterinary medicine. In addition to acute postoperative pain that requires management, limb amputations can result in chronic phantom limb pain in both human and veterinary patients. This phenomenon is not fully understood, but it is well documented that insufficient perioperative pain management increases the likelihood of developing chronic pain that can be difficult to manage in cats. 18 For this reason, an appropriate analgesic plan in the immediate postoperative period is particularly important for limb amputations. Multimodal analgesia, particularly involving the use of long-acting local anesthetics, has become more popular as a tool to control acute post-amputation pain and potentially reduce the impact of chronic neuropathic amputation-related pain.14,19 Recently, a paper evaluating the efficacy of LB in dogs undergoing limb amputation found that dogs receiving LB were discharged from hospital sooner than dogs that did not receive LB. 20 While these results show the promising benefit of LB usage as part of a multimodal opioid-sparing analgesic protocol specifically for limb amputation surgery, the efficacy in cats undergoing similar surgical procedures has not yet been evaluated.
The objective of this study was to evaluate the influence of LB on cats undergoing limb amputations to determine if LB administration in the perioperative period was associated with a decreased need for injectable opioids compared with traditional, systemic opioid-reliant pain protocols and adjuvant analgesics. To the authors’ knowledge, this is the first study to evaluate LB’s efficacy as an opioid-sparing analgesic compared with traditional analgesic protocols in cats undergoing limb amputation procedures. Our null hypothesis was that no statistically significant variation would be found regarding time to first postoperative alimentation, to discharge and to discontinuation of injectable opioids in cats that received LB compared with cats that did not receive LB. Our alternative hypothesis was that the LB group would have a statistically significant decrease in time to first postoperative meal, discharge from hospital and need for rescue injectable opioids compared with the non-LB group.
Materials and methods
All medical records between 2016 and 2022 at Michigan State University’s Small Animal Clinic were reviewed for cats undergoing any limb amputation. Cases with sufficient medical records to determine postoperative pain management and assessment for objective measurements of postoperative pain were included in this study.
Information on patient signalment, presenting physical findings (including ambulatory status on affected limb), locoregional block administration and LB usage were recorded. Locoregional block administration (consisting of a sodium channel blocker ± full mu opioid) was at the discretion of the operating surgeon and anesthesiologist; exact dosages of the drugs utilized were not provided in the medical records. LB, when utilized, was administered at a dosage of 5.3 mg/kg into all tissue layers during closure. The duration of hospitalization (from time of surgery to time of discharge) and time to first postoperative meal were recorded. Meals were offered as soon as nursing staff deemed the cats were sufficiently recovered from general anesthesia to be safely fed without risk of aspiration or upper airway obstruction, a time period that was not standardized between patients. Subsequent meals were then offered every 8 h until discharge.
Injectable analgesics were subdivided into ‘opioids’ and ‘adjuvant’ categories, where ‘adjuvant’ analgesics included non-opioid injectable analgesics, such as dexmedetomidine and ketamine constant rate infusions given in the postoperative period. If patients received any injectable analgesics, the type, dosage and duration of administration were recorded. All cats that received injectable opioids received a full mu or partial mu agonist as either a constant rate infusion or intermittent injection. Oral analgesics were divided into ‘non-steroidal anti-inflammatory drugs’ (NSAIDs) and ‘adjuvant’ medications, which included oral analgesics such as gabapentin and transmucosal buprenorphine. Buprenorphine was classified as an adjuvant oral analgesic rather than opioid medication for the purposes of this study owing to the lower bioavailability (approximately 20–30%) of the transmucosal route of administration in cats compared with injectable administration.21,22 Administration of both injectable and oral analgesics were non-standardized in the postoperative period; however, of the drugs that patients received in the postoperative period before discharge from hospital, the time from surgery until first dose was recorded.
The data were examined for outlier and distributional attributes. The outcome variables were highly skewed so non-parametric tests were used. The Wilcoxon rank-sum test was used to identify statistically significant differences (P ⩽0.05) between the two treatment groups regarding time until first postoperative meal, discontinuation of injectable opioids and discharge from hospital. Fisher’s exact test was used to evaluate for statistically significant differences (P ⩽0.05) between the two treatment groups for the usage of any additional non-opioid systemic analgesics in the postoperative period. The statistical analysis was performed using SAS 9.4 (SAS Institute).
Results
A total of 34 medical records of cats undergoing limb amputations were identified; four cats were excluded owing to incomplete medical records and one cat was excluded from analysis as a result of having a pain diffusion catheter utilized for postoperative analgesia. The final data included 29 patients undergoing limb amputation surgery between 27 July 2016 and 21 November 2022. Of the 29 cats, 12 (41%) were female, 17 (49%) were male, three (10%) were intact and 26 (90%) were neutered. The median age of cats undergoing amputation was 6 years (range 2–12). The mean (± SD) body weight was 4.6 ± 1.4 kg. The patient population comprised the following cat breeds: one Bengal, two domestic longhair, one domestic mediumhair, 23 domestic shorthair and two Siamese cats. In total, 7/29 (24%) of the study population did not receive LB and 22/29 (76%) cats received LB. A thorough breakdown of limb amputation location and all perioperative analgesics between the two treatment groups is provided in Table 1. Because of the small sample size and lack of standardized analgesic administration protocols, only the need for adjuvant injectable analgesics was evaluated for significance between the treatment groups. No difference in the need for additional injectable analgesia was identified between LB and non-LB cats (Table 1).
Distribution of pelvic and forelimb amputations between LB and non-LB treatment groups
Data are n (%). Summary of all analgesic medications administered in the postoperative period until discharge in the LB and non-LB treatment groups. Epidurals were administered at the discretion of the anesthesia team and consisted of a non-standardized dosage of a sodium channel blocker ± full mu agonist opioid. Intraoperative nerve blocks were given at the discretion of the operating surgeon and consisted of a sodium channel blocker. All cats that received injectable opioid medications received a full mu or partial mu agonist as either a constant rate infusion or intermittent injection at the discretion of the operating surgeon. The cats that received an additional adjuvant injectable analgesic received a combination of a ketamine constant rate infusion (1–5 µg/kg/min) and/or a dexmedetomidine constant rate infusion (1 µg/kg/h) at the discretion of the operating surgeon. All cats that received postoperative oral NSAIDs received robenacoxib at a dosage of 1 mg/kg PO q24h. All cats that received postoperative oral adjuvant medications received a combination of gabapentin at a dosage of 10 mg/kg PO q8–12h and/or transmucosal buprenorphine at a dosage of 0.01 mg/kg transmucosal q8–12h. LB = liposomal bupivacaine; NSAID = non-steroidal anti-inflammatory drug
The median times to first postoperative meal, hospital discharge and discontinuation of injectable opioids are summarized in Figures 1–3. Of the study population, 6/29 (5/22 LB and 1/7 non-LB) cats did not eat at all during their hospitalization period and were therefore excluded from analysis regarding comparison of timing to alimentation; however, they were included in all other analyses. No nausea or other gastrointestinal adverse effects were noted in any of the cats during hospitalization. No statistically significant differences were found between the two treatment groups for all measured outcome variables. For this reason, we failed to reject the null hypothesis.
Comparison of hours to eating postoperatively between cats that received LB and those that did not. The median time to first alimentation was 5.0 h (IQR 4.0–24.0) for the non-LB group and 6.0 h (IQR 4.0–8.0) for the LB group. No statistically significant difference was identified between the two groups using a Wilcoxon rank-sum test (P = 0.92). IQR = interquartile range; LB = liposomal bupivacaine
Comparison of hours to discharge postoperatively between cats that received LB and those that did not. The median time to discharge was 42.0 h (IQR 23.0–64.0) for the non-LB group and 25.0 h (IQR 20.0–39.0) for the LB group. No difference was identified between the two groups using a Wilcoxon rank-sum test (P = 0.16). IQR = interquartile range; LB = liposomal bupivacaine
Comparison of hours to discontinuation of injectable opioids postoperatively between cats that received LB and those that did not. The median time to discontinuation was 22.0 h (IQR 18.0–64.0) for the non-LB group and 18.0 h (IQR 14.0–25.0) for the LB group. No difference was identified between the two groups using a Wilcoxon rank-sum test (P = 0.15). IQR = interquartile range; LB = liposomal bupivacaine
Discussion
Cats receiving LB were slightly more likely to discontinue injectable opioids and leave the hospital sooner (Figures 1–3). They also needed less rescue adjuvant analgesics compared with non-LB cats; however, none of these findings were statistically significant.
Delayed timing to a cat’s first postoperative meal is a behavioral change that could be attributed to uncontrolled surgical pain as well as a documented side effect from systemically administered opioids.2,3 Unfortunately, owing to the retrospective nature of this study, inappetence secondary to opioid-induced nausea or appetite suppression was impossible to discriminate from inappetence secondary to pain. We anticipated that cats within the non-LB group would (1) rely more heavily on injectable opioids for postoperative analgesia and (2) would subsequently show more signs associated with nausea that delayed their timing to first postoperative meal; however, no significant differences in incidence of vomiting/nausea were identified in the study population. Although this study did not find a statistically significant difference in time to eating between treatment groups or time to discontinuation of injectable opioids, cats receiving LB tended to eat slightly earlier and require less injectable opioids than those without LB. This finding corresponds to prior studies evaluating the efficacy of LB and systemic analgesics in veterinary patients, where, despite anticipating a greater degree of systemic side effects associated with more frequently administered rescue systemic opioid medications, no demonstrable change in nausea or eating frequency was identified.4,16 Because a small trend towards difference was noted (as well as a comparatively wider range of values within the non-LB group in Figures 1–3), we postulate that a more significant disparity between treatment groups may have been identified with a larger study population.
Another potential reason for the lack of significant difference in time to eating is due to cat behavioral changes commonly encountered when staying in hospital. Cats at the authors’ hospital were placed in the intensive care ward where they experienced frequent handling and administration of medications. The relatively high level of environmental stress frequently results in inappetence despite appropriate pain control. Of the 6/29 cats that did not eat during their hospital stay, three LB cats were discharged within 24 h of surgery because the lack of appetite was considered to be secondary to stress rather than any documented signs of pain. As a result of the retrospective nature of this study, a standardized feeding schedule was not established among patients. Although all patients were offered food every 8 h, the time to the first offered meal varied among patients and was based upon their level of recovery from general anesthesia rather than at a specific time point. This limitation is another potential reason for the lack of statistical significance between the study groups, as cats may have eaten earlier than the recorded time but did not simply because food was not made available to them until a later time. Similarly, the time to discharge was not standardized within the study population and cats were frequently discharged before the 72 h period of LB efficacy was over, which means that any changes in cat behaviors that could be attributed to increasing pain as the LB wore off were not documented within the study period.
Part of the challenge of pain management in cats is the difficulty of accurate and objective pain scoring, as the majority of validated pain scoring methods rely on non-specific behavioral changes (self-isolation, decreased activity, increased or decreased grooming, etc) making it difficult to differentiate between non-painful stress and true pain. 2 The Feline Grimace Scale is one example of a pain-scoring method developed specifically to aid in better identification and qualification of pain in cats based on changes in expression. Although it has been found to be an accurate form of pain scoring in the immediate postoperative period with minimal variance between observers, 3 it is currently under-utilized in most clinical settings and is not consistently utilized at the authors’ hospital. Previous studies have used the Feline Glasgow Composite Measure Pain Scale to provide an objective measurement of acute postoperative pain in cats after undergoing ovariohysterectomy and were able to determine that LB use provided equivalent pain relief to cats that received only robenacoxib for postoperative pain relief. 15 Unfortunately, the retrospective nature of our study precluded the use of the Feline Glasgow Composite Measure Pain Scale or Feline Grimace Scale. The lack of standardization of pain scoring may have contributed to the authors’ inability to detect any significant differences in pain between the two treatment groups. This highlights the need for objective pain scoring, particularly when evaluating acute surgical pain in cats, where signs of discomfort can be subtle and commonly confused with non-painful stress. 2
There was a significant variation in administration of epidurals, intraoperative nerve blocks, injectable analgesics and oral analgesics due to the lack of a standardized analgesic protocol for the study population. Some medications given as epidurals and/or intraoperative nerve blocks may have provided long-lasting analgesia into the immediate postoperative period, and thus may have contributed to the lack of differences in the measured outcome variables. Through the utilization of a more standardized analgesic protocol, future studies could avoid this potential confounding influence. In addition, as some reports in the human literature indicate that LB is not a superior analgesic to other local anesthetic techniques,23,24 a comparison of LB to a standardized protocol involving these shorter-acting local anesthetic techniques would be an interesting future topic for study.
Consequently, the main limitations of this study include its retrospective nature, the lack of use of a validated pain scoring method, variation in pain management protocols between surgeons (Table 1), non-standardized time to first offering of food in postoperative period, overall small population size, and the assumption that time to eating and discharge were based solely on appropriate levels of pain management for patients. Future prospective studies could address these limitations through the development of a specific postoperative rescue analgesic protocol for a designated period of time before patient discharge, along with the use of a validated objective pain scoring method. Controlling variability in postoperative patient management (including time to discharge and analgesics administered) would likely provide stronger evidence of LB’s equivalency or improved efficacy as an opioid-sparing postoperative analgesic compared with traditional protocols with heavier reliance on systemic opioid medications.
Conclusions
The results of this study suggest that LB usage as part of a multimodal analgesic protocol in cats undergoing limb amputation surgery is associated with a decreased need for injectable opioids in the postoperative period. While not statistically significant, a trend was noted that cats receiving LB were discharged sooner, required a shorter duration of injectable opioids and needed less adjuvant systemic analgesic medications to manage their postoperative pain. Though not documented in this study, it is known that systemic opioids can contribute to postoperative morbidity in surgical patients, including, but not limited to, inappetence (potentially resulting in prolonged hospitalization for parenteral feeding), ileus, sedated/decreased mentation and dysphoria. LB, as a long-acting local anesthetic, has not been documented to have any increased risk of systemic side effects when utilized according to manufacture instructions. Future prospective clinical studies are still needed for the further evaluation of LB as a safe and effective component of an opioid-sparing multimodal analgesic protocol, especially when compared to alternative shorter-acting local anesthetic techniques.
Footnotes
Author note
This paper was presented in part as a poster presentation at the 2023 American College of Veterinary Surgeons – Surgery Summit.
Conflict of interest
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical approval
This work described in this manuscript involved the use of non-experimental animals (owned or unowned). Established internationally recognized high standards (‘best practice’) of veterinary clinical care for the individual patient were always followed and/or this work involved the use of cadavers. Ethical approval from a committee was therefore not specifically required for publication in JFMS. Although not required, where ethical approval was still obtained, it is stated in the manuscript.
Informed consent
Informed consent (verbal or written) was obtained from the owner or legal custodian of all animal(s) described in this work (experimental or non-experimental animals, including cadavers, tissues and samples) for the procedure(s) undertaken (prospective or retrospective studies). No animals or people are identifiable within this publication, and therefore additional informed consent for publication was not required.
