Implementation of an opioid-sparing protocol utilizing liposomal bupivacaine and intravenous ketorolac for pain management after living kidney donation

Abstract

BACKGROUND

Opioids are commonly used for management of post-operative pain in living kidney donors. Reducing exposure to opioids is desirable to minimize risk of dependence and potential side effects such as nausea, vomiting, and constipation which may delay discharge. Liposomal bupivacaine, ketorolac, and scheduled acetaminophen have all demonstrated efficacy for management of post-operative pain in this population.

AIM

To assess the efficacy and safety of an opioid-sparing protocol utilizing a multimodal pain management approach in living kidney donors post-nephrectomy.

METHODS

Single-center, retrospective chart review study examining 52 living kidney donors (26 pre-protocol implementation, 26 post-protocol implementation) from May 24^th, 2019 to September 27^th, 2023. Patients in the post-protocol group received intraoperative liposomal bupivacaine, hydromorphone PCA (until able to tolerate oral medications), 15 mg of intravenous ketorolac every 6 hours for 3 doses, and scheduled oral acetaminophen, in addition to oxycodone as needed for moderate to severe pain. The primary endpoint was oral morphine equivalent (OME) use within 48 hours post-surgery. Secondary endpoints include average daily pain scale within 48 hours post-surgery, length of stay (LOS) (days), and incidence of new acute kidney injury (AKI) or gastrointestinal (GI) bleed during admission per provider. Differences between the pre- and post-protocol implementation groups were compared utilizing the exact Wilcoxon test for continuous variables and either the Fisher’s Exact or χ² test for categorical variables.

RESULTS

Patients in the pre-protocol implementation group received more OME (mg) within 48 hours post-surgery when compared to the post-protocol group (median: 84.5 vs 69.0). The median of total OME over the course of admission was numerically greater the pre-protocol group (105.0 vs 69.0), and was significantly more per LOS (41.3 vs 25.7, P = 0.02). Average daily pain score was not statistically significantly different between the two groups on post-operative day 1 (median: 5.3 vs 4.4; P = 0.43) and post-operative day 2 (median: 4.7 vs 5.2; P = 0.96). No significant differences were found in provider-identified incidences of AKI or GI bleeding during admission. There was no difference in serum creatinine at the time of discharge between the two groups.

CONCLUSION

A multimodal, opioid-sparing pain management protocol was as effective for pain control and resulted in significantly less opioid daily exposure over LOS. No adverse events were found related to use of ketorolac in patients undergoing donor nephrectomy. Our findings suggest that an opioid-sparing protocol is both safe and effective at minimizing opioid exposure and managing post-operative pain within the first 48 hours post-surgery.

Key Words: Opioid; Pain management; Bupivacaine; Ketorolac; Nephrectomy; Living Donation; Renal transplant

Core Tip: Opioids are commonly used for management of post-operative pain in living kidney donors. Reducing exposure to opioids is desirable to minimize risk of dependence and potential side effects such as nausea, vomiting, and constipation which may delay discharge. Liposomal bupivacaine, ketorolac, and scheduled acetaminophen have all demonstrated efficacy for management of post-operative pain in this population. The purpose of this retrospective chart review study is to assess the efficacy and safety of an opioid-sparing protocol utilizing a multimodal pain management approach in living kidney donors post-nephrectomy.

INTRODUCTION

Approximately 800000 patients in the United States are living with end stage renal disease[1]. According to national data provided by the Organ Procurement and Transplantation Network (UNOS), 27332 kidney transplants were performed in 2023[2]. While the majority of transplants utilized a deceased donor, approximately 24% involved a living donor[2]. Living donation is frequently altruistic with no therapeutic benefit to the donor except in rare situations such as patients with nutcracker syndrome. In these cases, the resected kidney may be donated to a suitable recipient, providing symptomatic relief to the donor and significant benefit to the recipient[3].

The average length of stay (LOS) for a patient undergoing donor nephrectomy is usually brief and, in some cases, may be as short as a single day[4]. Management of post-operative pain remains a priority in these patients with the goal of relieving pain while minimizing adverse effects. A commonly recommended approach to achieve this goal is the use of a multimodal pain regimen, which involves center-specific variations on combined use of acetaminophen, non-steroidal anti-inflammatory medications (NSAIDs), ketamine, gabapentin, and techniques such as regional or neuroaxial anesthetics[5]. Monitoring required for these therapies is typically limited to assessment of patient pain and concerns for acute kidney injury (AKI) or bleeding associated with NSAIDs.

Opioid minimization - particularly in patients naïve to their use - is another cited benefit of a multimodal pain management approach, as these medications carry a high risk for addiction and are associated with adverse effects such as nausea and constipation[6]. Recent statistics provided by the Centers for Disease Control and Prevention cite an increase in opioid-related death rates by over 15% from 2020 to 2021, with at least 220 overdose-related deaths per day[7]. In an effort to curtail the ongoing opioid epidemic, multidisciplinary stewardship is required to circumvent usage and prescription of these medications other than when absolutely necessary. Reduction in opioid usage is particularly desirable in living kidney donors, who tend to be younger, healthier individuals with minimal prior exposure[8].

Our center utilizes a multimodal, opioid-sparing approach towards pain management in patients undergoing laparoscopic donor nephrectomy (Table 1). We do not withhold opioids if their use is required, but our goal is to use the minimum necessary amount for adequate pain relief. This approach was implemented in May of 2019 and continues to current date. The purpose of this retrospective chart review study is to assess the efficacy and safety of this pain management protocol compared to a cohort of patients undergoing donor nephrectomy prior to its implementation.

Table 1 Multimodal, opioid-sparing pain management protocol.

Agent	Time of initiation	Dosing
Liposomal bupivacaine 13% injection (13.3 mg/mL)	Intra-operative	133 mg (10 mL) subcutaneously on each side of incision
Ketorolac	Post-operative day 0	15 mg IV Q6H for 3 doses
Hydromorphone IV PCA1	Post-operative day 0	Basal rate: None
		PCA bolus: 0.1 mg
		Lockout interval: 10 minutes
		Four house dose limit: 2.4 mg
Acetaminophen	Post-operative day 1	650 mg PO Q6H
Oxycodone	Post-operative day 1	5 mg PO Q4H as needed for moderate pain
		10 mg PO Q6H as needed for severe pain

¹Discontinued when patient able to tolerate oral medication.

MATERIALS AND METHODS

Patients and study design

This single-center, retrospective study included 52 living kidney donors (26 pre-protocol implementation, 26 post-protocol implementation) from May 24^th, 2019 to September 27^th, 2023. All patients in the post-protocol group received intraoperative liposomal bupivacaine, hydromorphone PCA (until able to tolerate oral medications), post-operative IV ketorolac for 3 doses, and post-operative scheduled oral acetaminophen in addition to oxycodone as needed for moderate to severe pain (Table 1). There were no clinically significant differences in the demographics between the pre- and post-protocol implementation groups (Table 2).

Table 2 Summary of demographic characteristics of study sample by group (n = 52), n (%).

	Pre-protocol group (n = 26)	Post-protocol group (n = 26)
Gender
Female	21 (80.8)	18 (69.2)
Male	5 (19.2)	8 (30.8)
Age (years)
Median [IQR]	47.0 (33.0, 58.0)	49.0 (40.0, 58.0)
≤ 45	12 (46.2)	11 (42.3)
Admission weight (kg)
Median [IQR]	76.8 (64.1, 87.0)	76.8 (68.0, 96.2)
Ethnicity
African-American	7 (26.9)	5 (19.2)
Caucasian	14 (53.8)	14 (53.8)
Hispanic	5 (19.2)	1 (3.8)
Unknown	0 (0.0)	6 (23.1)

The primary endpoint for this study was oral morphine equivalent (OME) use within 48 hours post-surgery. Secondary endpoints included average daily pain scale within 48 hours post-surgery, LOS (days), and incidence of new AKI or gastrointestinal (GI) bleeding during admission as identified by provider documentation.

Statistical analysis

Data were expressed as counts and percentages for categorical variables and median inter-quartile range (IQR) for continuous variables. Differences between the pre- and post-protocol implementation groups were compared utilizing the exact Wilcoxon Rank-Sum test for continuous variables and either Fisher’s Exact with mid-P value or χ² test for categorical variables. P-values less than 0.05 were considered statistically significant. SAS version 9.4 (SAS Institute Inc., Cary, NC, United States) was used for all the data analyses.

RESULTS

A total of 52 living kidney donors were included in the analysis, with 26 patients in the pre-protocol group and 26 in the post-protocol group. Baseline demographic characteristics were comparable between the two cohorts, including median age, admission weight, and gender distribution (Table 2). The median age IQR was 47.0 (33.0-58.0) years in the pre-protocol group and 49.0 (40.0-58.0) years in the post-protocol group; most donors in both groups were female.

Primary outcome

Patients in the post-protocol group had a lower median OME use in the first 48 hours post-surgery compared with patients in the pre-protocol group-69.0 (18.0-112.5) mg vs 84.5 (42.0-133.0) mg, respectively (Table 3). Total OME for the entire admission was also lower in the post-protocol group [69.0 (34.0-121.5) mg] than in the pre-protocol group [113.8 (50.0-185.0) mg] (P = 0.043).

Table 3 Medication usage by study group (n = 52).

	Pre-protocol group (n = 26)	Post-protocol group (n = 26)
Acetaminophen received in first 48 hours post-operatively (mg)	3250.0 (2000.0, 4000.0)	2600.0 (1950.0, 4950.0)
OME received in first 48 hours post-operatively	84.5 (42.0, 133.0)	69.0 (18.0, 112.5)
Total OME for admission	113.8 (50.0, 185.0)	69.0 (34.0, 121.5)
OME per LOS (days)	37.9 (18.0, 52.8)	25.7 (9.4, 37.5)
LOS (days)	3.0 (2.0, 3.0)	3.0 (2.0, 3.0)
Mean pain score (POD#1)	5.3 (4.0, 6.4)	4.4 (3.6, 6.7)
Mean pain score (POD#2)	4.7 (3.7, 6.3)	5.2 (2.7, 6.5)
Mean pain score for overall LOS1	4.7 (3.5, 5.6)	4.4 (2.7, 5.9)
Doses of ketorolac received	0.0 (0.0, 0.0)	2.0 (1.0, 3.0)
Received liposomal bupivacaine	0 (0.0%)	23 (88.5%)

¹Mean pain score for overall length of stay had 2 missing values.

Median (IQR) for continuous variables and frequency (%) for categorical variables. OME: Oral morphine equivalent; LOS: Length of stay.

Secondary outcomes

Both cohorts had a median LOS of 3.0 (2.0-3.0) days (Table 3). Mean pain scores were generally similar. On postoperative day (POD) 1, the median pain score was 5.3 (4.0-6.4) in the pre-protocol group versus 4.4 (3.6-6.7) in the post-protocol group, while on POD 2, median scores were 4.7 (3.7-6.3) vs 5.2 (2.7-6.5), respectively. Notably, the post-protocol group received a median of two doses of ketorolac (1.0-3.0), whereas no patients in the pre-protocol group received ketorolac. In addition, 23 (88.5%) patients in the post-protocol group received liposomal bupivacaine, in contrast to none in the pre-protocol group (Table 3).

Safety endpoints

Admission and discharge serum creatinine values were similar between groups. However, provider concern for AKI was documented for four (15.4%) patients in the pre-protocol group and for none in the post-protocol group. Similarly, two (7.7%) patients in the pre-protocol group had provider-documented GI bleeding or other major bleeding events, compared with no patients in the post-protocol group (Table 4). Overall, these findings suggest that the new opioid-sparing pain management protocol did not increase the incidence of major adverse events during admission.

Table 4 Safety endpoints by study group (n = 52).

	Pre-protocol group (n = 26)	Post-protocol group (n = 26)
Admission serum creatinine (mg/dL)	0.8 (0.7, 0.9)	0.9 (0.8, 1.0)
Discharge serum creatinine (mg/dL)	1.2 (1.0, 1.4)	1.3 (1.2, 1.5)
Provider concern for AKI during admission (%)
No	22 (84.6)	26 (100.0)
Yes	4 (15.4)	0 (0.0)
Provider concern for GI bleeding (or any other major form of bleeding) (%)
No	24 (92.3)	26 (100.0)
Yes	2 (7.7)	0 (0.0)

Median (IQR) for continuous variables and frequency (%) for categorical variables. AKI: Acute kidney injury; GI: Gastrointestinal.

DISCUSSION

Post-operative care for patients undergoing donor nephrectomy is focused on observation for surgical complications and management of post-operative pain. Opioid medications remain a mainstay of pain management due to their fast onset and reliable efficacy, but concerns limiting their use include adverse effects such as nausea and constipation, as well as their addictive potential. Multimodal approaches to pain management in this patient population have demonstrated a wide range of potential benefits, including lower opioid consumption, improved pain scores, and shorter LOS[9-11]. A multimodal approach to pain utilizing liposomal bupivacaine with a goal of opioid minimization has also demonstrated significantly less nausea and vomiting with 72 hours[11].

Another key therapy utilized in post-operative pain management is ketorolac, an NSAID medication which may be administered intravenously with rapid onset of efficacy. Common concerns associated with NSAIDs include increased risk for acute kidney or bleeding, both of which are listed as warnings on the package insert for ketorolac[12]. Despite these theoretical concerns, multiple studies have established the safety and efficacy of intravenous ketorolac in the setting of live donor nephrectomy[13-15]. Studies which have identified post-operative administration of ketorolac as a risk factor for worse renal function at 1-year post-donation included a large number of patients who received significantly higher doses than those used at our institution[16,17].

Our approach to multimodal pain control for living kidney donors involves intra-operative injection of liposomal bupivacaine at the site of incision, immediate post-operative use of intravenous ketorolac, patient-controlled analgesia with intravenous hydromorphone which is transitioned to oral oxycodone as soon as able, and oral acetaminophen (Table 1). The goal of our protocol is not to avoid opioid use entirely but to minimize total exposure through effective use of other therapies.

In assessing this protocol, we hypothesized that outcomes within the first 48 hours would be of greatest importance as this would be the period of time when patients would require the most rigorous pain control. A similar amount of acetaminophen was utilized in both groups within the first 48 hours (P = 0.69), indicating that the results observed during this time period were related to hydromorphone/oxycodone, ketorolac, and liposomal bupivacaine. While opioid exposure in this time interval was similar between the pre- and post-protocol groups, there was numerically less opioid exposure per LOS and significantly less total opioid usage overall. Mean pain scores for the first two post-operative days and overall LOS were similar between the pre- and post-protocol groups despite significantly reduced opioid usage in the post-protocol group (Table 3).

As a point of comparison, an abstract was presented by Yang et al[18] which observed significantly reduced opioid usage in the first 24 hours post-operatively in patients receiving liposomal bupivacaine (50.1 OME vs 84.9 OME in their liposomal bupivacaine group vs non-liposomal bupivacaine group, respectively). We assessed the first 48 hours post-operatively and noticed a sustained difference (69.0 OME vs 84.5 OME in our post-protocol vs pre-protocol group, respectively) (Table 3). While the window of time for potential opioid administration we assessed was twice that of Yang et al[18], we observed similar total OME usage in the observed timeframe which may be reflective of further improvement in pain control with addition of ketorolac to liposomal bupivacaine.

Serum creatinine at admission and time of discharge were similar between both groups, and we did not find any provider concern for AKI in the post-protocol group (Table 4). The elevated serum creatinine in both groups at the time of discharge is expected in patients undergoing donor nephrectomy, who experience immediate, temporary decreases in glomerular filtration associated with loss of nephron mass[19]. There was also no concern for GI bleeding or any other major form of bleeding. Our findings add to the existing body of evidence that short-term post-operative use of intravenous ketorolac is both safe and effective in patients undergoing donor nephrectomy.

There are several limitations to this study worth noting. The first of these limitations is the retrospective nature of the study which necessitates a reliance on provider documentation. Due to this limitation, we were only able to draw conclusions about outcomes which were accurately and consistently documented. Therefore, we were not able to assess certain subjective parameters such as nausea. Our sample size was relatively small at 52 patients overall, and our sample of pre-protocol patients involved the most recent 26 living donors prior to protocol implementation. While this is not a truly randomized sample, we feel that this ensures the remainder of their care was as similar to the post-protocol group as possible. Another limitation related to this study is our inability to make a long-term comparison of renal function between the two groups and assess whether usage of ketorolac was associated with any negative long-term effects. This is in part due to a lack of sufficient data in the post-protocol group related to compliance with post-donation follow-up. However, given the retrospective nature of this study, the limited total dose of ketorolac we utilized, and the small population size we assessed, it would be difficult to correlate ketorolac usage to long-term decline of renal function. Additionally, a post-hoc analysis of a review separate from ours was performed in a similar population which did not observe any negative impact on renal function at one-year post-donation in patients receiving ketorolac[15]. Lastly, the conclusions drawn from this data are applicable only to the inpatient setting in the immediate post-operative period for a population similar to ours.

CONCLUSION

Overall, this retrospective review demonstrates successful implementation of a multimodal, opioid minimizing pain management protocol for patients undergoing donor nephrectomy. We found that implementation of such a protocol resulted in significantly lower total OME exposure, adequate pain control, and minimal adverse events of concern.