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Enhanced recovery after cystectomy in patients with preoperative narcotic use

Introduction: The aim of this study was to evaluate the outcomes of radical cystectomy with an enhanced recovery after surgery (ERAS) protocol in patients with a history of chronic preoperative narcotic use compared to narcotic-naive patients. Methods: We identified 553 patients who underwent open radical cystectomy with ERAS. Preoperative narcotic use was identified in 34 patients who were then matched to 68 narcoticnaive patients. Postoperative outcomes, opioid use, and visual analog scale (VAS) pain scores were analyzed and compared. All routes of opioid use were recorded and converted to a morphine equivalent dose (MED). Results: Patients with preoperative narcotic use reported higher median VAS pain scores per day (POD1: 5.2 vs. 3.9, p=0.003; POD2: 5.1 vs. 3.6, p<0.001; POD3: 4.6 vs. 3.8, p=0.004) and used significantly more opioids (median MED) per day (POD1: 13.2 vs. 10.0, p=0.02; POD2: 11.3 vs. 6.4, p=0.003; POD3: 10.2 vs. 5.0, p=0.005) following surgery. Preoperative narcotic users were noted to have a significantly higher incidence of 90-day readmissions (41.2% vs. 20.6%, p=0.03). There was no difference in median hospital stay (4 vs. 4 days, p=0.6), 30or 90-day complications (64.7% vs. 60.3%, p=0.8 and 82.4% vs. 75.0%, p=0.4, respectively) or gastrointestinal complications (29.4% vs. 26.5%, p=0.8), including postoperative ileus (11.8%


Introduction
With an estimated 81,400 new cases diagnosed in 2020, bladder cancer is one of the most common malignancies in the United States (U.S.). Moreover, 17,980 patients are estimated to die from bladder cancer in 2020, making it one of the most lethal urologic diseases. 1 Radical cystectomy (RC) with urinary diversion is the gold standard management for patients with muscle invasive or high-risk non-muscle invasive disease. RC is a morbid procedure with historical early complication rates of up to 67% and length of stay of up to 9-11 days. 2,3 The perioperative management of patients undergoing RC is complex and has seen major improvement in recent years owed to the increased acceptance of enhanced recovery after surgery (ERAS) protocols. 4 We have previously shown the benefit of an ERAS protocol in reducing length of stay without an increase in complications or readmission rates. 5 ERAS protocols are multimodal pathways that streamline all elements of perioperative care, including pre, intra, and post-operative interventions. A major focus is on the minimization of narcotic pain management and the use of μ opioid antagonists to accelerate gastrointestinal recovery. 6 As we strive to improve ERAS protocols and subsequent outcomes, we must target all modifiable factors and better understand non-modifiable ones. In 2017, the U.S. Department of Health and Human Services declared an opioid epidemic. 7 Over 2 million patients abuse opioids yearly, with an annual incidence of more than 200,000 new users and 16,000 deaths from opioid overdose. 8 The crisis is widespread and affects many patients undergoing urologic procedures including RC. The efficacy of modern treatment practices on patients with a history of preoperative narcotic use needs to be better understood. In this study, we investigate the effect of preoperative narcotic use on outcomes in patients undergoing RC with an enhanced recovery protocol.

Study population
Using our prospectively maintained, institutional review board-approved bladder cancer database, we identified all patients with preoperative narcotic use who underwent open RC, pelvic lymph node dissection and urinary diversion for urothelial carcinoma with intent to cure from June 2012 to June 2017, the initial 5 years after implementation of our ERAS protocol. Preoperative narcotic users were defined as those having an active prescription for narcotics for ≥30 days prior to surgery. Narcotic users were identified through preoperative history and physical documentation and meticulous chart review was then performed. Inactive prescriptions

Results
A total of 722 open radical cystectomies were performed during the study period. Of these, 553 were for curative intent and enrolled in the ERAS protocol. Preoperative narcotic use was identified in 34 (6.09%) patients. Indications for preoperative narcotic use included chronic arthritic conditions in 16 (47.1%), neurologic disease in 3 (8.8%), urologic related pain in 9 (26.5%) and other causes in 6 (17.6%). Narcotic users were matched to 68 patients with no reported history of narcotic use. Demographic characteristics of the matched cohorts are summarized in Table 1.

Outcomes
Preoperative narcotic users were noted to have a lower estimated blood loss during their operations (mean 462.3±350.0 ml vs 523.8±318.4 ml, p=0.04). There was no significant difference in operative time (mean 5.5±1.5 hours vs 5.6±1.2 hours, p=0.170) or median length of stay (4 days vs 4 days, p=0.6) between the two groups.
Readmissions were similar at 30 days (20.6% vs 13.2%, p=0.3), but preoperative narcotic users did have a higher rate of 90-day readmissions when compared to narcotic naïve patients (41.2% vs 20.6%, p=0.03). Complications leading to 90-day readmissions were stratified based on etiology and are summarized in Table 3. Narcotic users were noted to have a higher proportion of major complications requiring 90-day readmission compared to narcotic naïve patients (50.0% vs 28.6%, respectively, p=0.26), though not significantly so. The most common complications resulting in readmission amongst both groups were renal/electrolyte causes (dehydration), followed by infectious and then GI-related causes.

CUAJ -Original Research
Ghodoussipour et al Post-cystectomy in narcotic users vs. narcotic-naive patients 5 © 2021 Canadian Urological Association

Discussion
The opioid epidemic exposes urologists to more and more patients with a history of narcotic use before surgery. Chronic preoperative narcotic use has been shown to be associated with higher complications and worse functional outcomes following non-urological surgeries, [12][13][14] though the data is sparse in urology literature including radical cystectomy. Given the complexity and associated morbidity with radical cystectomy and urinary diversion, more information in this unique patient subset is needed. Previous studies have shown that ERAS protocols not only decrease hospital stay, but also decrease in-hospital pain, narcotic use and GI complications when compared to traditional recovery protocols. 5,9,15 In a prior report on pain management following RC at our institution, we found that ERAS patients used significantly less opioids (4.9 vs 20.7 MEDs, p<0.001) and had a lower rate of POI when compared to a pre-ERAS cohort (7.3% vs 22%, p=0.03). 9 However, we excluded narcotic users in that study. In the current study, our primary goal was to explore the effects of an ERAS protocol in patients with a preoperative history of narcotic use, specifically to determine if they experience the same benefits as those patients without a history of recent narcotic use.
To compare in-hospital narcotic requirements, a MED was used. 11 We found that patients with preoperative narcotic use had significantly more postoperative pain than narcotic naïve patients and required significantly more opioids following surgery. These results are in line with prior studies that suggest opioids may induce hyperalgesia (OIH). [16][17][18] Chu et al. provided evidence for the development of OIH when they tested 6 patients after one month of oral morphine therapy for lower back pain and found significant hyperalgesia to experimental cold pain. 16 While the methodology of studies testing OIH vary, the mechanism is thought to be due to neuroplastic changes in the peripheral and central nervous systems that lead to sensitization of pronociceptive pathways. 17 Ren et al. performed a study in 54 opiate addicts and 46 healthy controls and noted hyperalgesia in the addicts. They also found that pain distress was positively correlated with opiate craving. 18 The association between exaggerated pain responses and drug craving may explain the findings in our study.
Despite the higher pain scores and greater in-hospital opioid use in preoperative narcotic users, there was no significant difference in clinical outcomes aside from renal/electrolyte-related complications and readmissions within 90 days. There were more high-grade complications leading to readmission in the preoperative narcotic users compared to narcotic naïve patients, but we were unable to identify a significant difference probably due to the limited sample size of readmitted patients. The majority of readmissions in preoperative narcotic users were due to the high-grade renal/electrolyte complications (35.7% compared to 21.4% in the narcotic naïve group). This could be related to the effect of narcotics on the small and large bowel transit that will be resulted in the increase of fluid absorption, third spacing, and fluid/electrolyte imbalance. A recent report showed 142,557 emergency department visits for opioid overdose in the U.S. in 2017 alone, 19 but we were unable to attribute any of our readmissions to opioid overdose.

CUAJ -Original Research
Ghodoussipour et al Post-cystectomy in narcotic users vs. narcotic-naive patients 6 © 2021 Canadian Urological Association Interestingly, we did not find significant differences in GI complications amongst our two groups. A focus on GI-related complications is particularly important as the link between narcotic use and bowel function is clear. Previous studies have shown that an increased daily dose of narcotics and increasing days on narcotics both predict POI and length of stay. 10,20,21 The overall GI complication rate in our study was 29.4% in preoperative narcotic users and 26.5% in narcotic naïve patients (p=0.82), while rate of POI was 11.8% and 20.6% (p = 0.26) in the respective groups.
Another reason to emphasize GI complications is that prior studies suggest that these represent the most common reason for prolonged length of stay after radical cystectomy. 22 The median length of stay in both groups was 4 days and not different from prior reports from our institutional ERAS protocol. 5 While the previously referenced studies found increased POI and length of stay in narcotic users or those who received greater narcotics in hospital, our patient cohort is unique as all patients were treated within an ERAS protocol. There are various measures in our protocol that aim to mitigate postoperative stressors, specifically GI-related ones. There is evidence to support many of these measures including lack of bowel preparation, no nasogastric tube, and early feeding. [23][24][25] However, the strongest evidence-based intervention in our protocol is the use of pre-and peri-operative alvimopan, a μ opioid receptor antagonist that has been shown to decrease rates of POI, length of stay, and cost after radical cystectomy. 26,27 Alvimopan was approved by the U.S. Food and Drug Administration (FDA) in 2008 to accelerate GI recovery following partial large or small-bowel resection with primary anastomosis. 28 However, this approval came with a risk evaluation and mitigation strategy (REMS) label warning against its use in chronic narcotic users, defined as those who have been receiving opioids for >7 consecutive days. Thus, the only randomized controlled trial investigating alvimopan after RC excluded patients who had used narcotics preoperatively. 24 This REMS label came from preliminary results of a phase 3, double blind, placebo-controlled study that aimed to evaluate the long-term safety of alvimopan in patients with non-cancer related opioid induced bowel dysfunction (OBD). This study enrolled 805 patients with OBD and randomized them 2:1 to 538 receiving alvimopan 0.5 mg twice daily vs 267 who received placebo. The most common adverse events in the study were GI related, including abdominal pain and diarrhea (40% for alvimopan and 35% for placebo). Serious adverse events occurred in 13% of patients treated with alvimopan and in 11% with placebo, but 7 patients (1.3%) in the alvimopan arm suffered from myocardial infarction compared to 0 with placebo. The overall rate of serious cardiovascular (CV) events was 2.6% with alvimopan and 1.12% with placebo. All CV events occurred in patients with established or at high risk for CV disease. Still, these findings led to a hold on the drug by the FDA, which was temporary as other studies investigating the safety of alvimopan in OBD showed a myocardial infarction rate of 0.08% with alvimopan compared to 0.38% with placebo and all serious CV events 1.18% with alvimopan vs 0.96% with placebo. [29][30][31] The first of these three studies examined 168 patients with OBD

CUAJ -Original Research
Ghodoussipour et al Post-cystectomy in narcotic users vs. narcotic-naive patients 7 © 2021 Canadian Urological Association (minimum one month of opioid therapy) and found that alvimopan increased the proportion of patients having a bowel movement (BM) within 8 hours of starting the drug (54%, 43%, and 29% for alvimopan 1 mg, 0.5 mg and placebo, respectively, p<0.001). 29 The latter two studies randomized 1040 patients with OBD to alvimopan or placebo and found a significant increase in the rate of weekly BMs (p<0.001 for both studies). 30,31 An FDA panel later declared that the issue of CV safety was not class specific for μ opioid antagonists 32 and we have safely administered alvimopan to all patients enrolled in our ERAS protocol, irrespective of prior narcotics use. There was no difference in the cardiac complication rate in this study at 7.4% for narcotic naïve and 11.8% for preoperative narcotic exposed patients (p=0.48).
While the cause of increased 90-day readmissions cannot be explained by the results of our study, we do feel our results show that the cumulative effects of the measures included in our ERAS protocol level the playing field for patients with preoperative narcotic use such that they experience similar lengths of stay and complications, importantly GI-related ones, compared to narcotic naïve patients. The greater pain experienced by patients with preoperative narcotic use is an area for improvement and one that we have targeted with multidisciplinary management with our anesthesia colleagues. A recent change to our ERAS protocol since the time of this study has been multimodal prophylactic pain management with oral acetaminophen, celecoxib and gabapentin for 3 days prior to surgery. We are also trying to further improve outcomes through preoperative education sessions and potentially more effective therapeutics.
Our study is limited by the retrospective nature of preoperative narcotic use determination. We defined narcotic use before surgery as having an active prescription for ≥30 days, but we do not know how consistently patients were taking narcotics. Similarly, many patients who abuse narcotics may do so without a prescription. 33 A prospective identification of preoperative narcotic users could allow for quantities of preoperative narcotics to be recorded. Still our results provide a useful reference for surgeons who treat patients with the common scenario of a known but un-quantified history of narcotic use prior to surgery. Another limitation is that VAS scores are currently recorded at inconsistent time intervals and there is no way to collect objective pain information. However, this issue is not limited to our study and must be considered in any study assessing pain management. The strength of this study is to present a group of patients who underwent homogenous cystectomy and received similar perioperative care with as high as 88% compliance rate to our ERAS protocol. 34 Nevertheless, this sample is not representative of the complete ERAS cohort at our institution and includes only those with preoperative narcotics use and their matched cohort. Moreover, we did not evaluate differences in opioid consumption after discharge from the hospital. Such information will be useful to urologists as we combat the opioid epidemic.