A Preliminary Investigation: Alvimopan Use to Prevent Post-Operative Ileus after Radical Cystectomy with Urinary Diversion

doi:10.4236/oju.2013.37051

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Open Journal of Urology, 2013, 3, 272-275

Published Online November 2013 (http://www.scirp.org/journal/oju)

http://dx.doi.org/10.4236/oju.2013.37051

Open Access OJU

A Preliminary Investigation: Alvimopan Use to Prevent

Post-Operative Ileus after Radical Cystectomy with

Urinary Diversion

Benjamin F. Katz1*, Geoffrey S. Gaunay1, Basir U. Tareen2, Erik T. Goluboff1

1Department of Urology, Beth Israel Medical Center, New York, USA

2Department of Urology, Metropolitan Urologic Associates, Woodbury, USA

Email: *[email protected]

Received July 30, 2013; revised August 28, 2013; accepted September 5, 2013

License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly

cited.

ABSTRACT

Background: Postoperative ileus (POI) is a common and frustrating patient complication after a urinary diversion by

using a segment of bowel. Alvimopan is an oral selective antagonist to the peripheral µ-opioid receptor. Our study in-

vestigates the effect of alvimopan on POI in patients undergoing radical cystectomy. There are no documented studies

on alvimopan’s efficacy in urologic surgery literature. Methods: Approval from the Institutional Review Board was

obtained to conduct a retrospective review of patients’ records from August 2009 until August 2011. The study included

sixteen patients who had undergone radical cystectomy with ileal diversion. Exclusion criteria included patients with

chronic opioid use, previous colostomy or ileostomy, or significant comorbidities which could cause increased postop-

erative complications. Statistical analysis was performed to examine the association of alvimopan use with decreased

time to dietary advancement and decreased length of hospital stay. Results: The alvimopan group advanced their diet

more than 24 hours earlier in comparison with the alvimopan naïve group (P < 0.0433), and the alvimopan group had a

greater had a greater or 26% shorter hospital length (P < 0.0451) than one day. We showed a reduced risk of POI and

subsequent decreased hospital course length. There was no significant difference in readmission rate or need for na-

sogastric tube (NGT). Interpretation: To our knowledge we report one of the first uses of alvimopan in reducing POI

in the urological surgery literature. Our novel experience with using this drug is encouraging. Further research will ul-

timately determine if standard use of alvimopan to decrease POI in radical cystectomy with ileal diversion will be

implemented.

Keywords: Cystectomy; Urinary Diversion; Alvimopan; Ileus

1. Introduction

In 2009, there were over 70,000 new diagnoses of blad-

der cancer and more than 14,000 deaths, making bladder

cancer the 5th most common malignancy in the United

States [1]. Although chemotherapy and radiation therapy

are options for select patients, the gold standard for mus-

cle invasive disease continues to be radical cystectomy

with urinary diversion. Reconstruction of the urinary

tract is a necessity in order to preserve renal function.

There are numerous diversions and reconstructions de-

scribed in the literature and most require the use of small

or large bowel.

Radical cystectomy continues to be a morbid proce-

dure fraught with complications. Ileus is a common oc-

currence leading to patient discomfort and increased

length of hospital stay [2]. Post-operative ileus (POI) is

defined as a “transient impairment of bowel motility” [3].

This condition may lead to nausea, vomiting, prolonged

hospital stay, bowel distention, abdominal pain, and, in

severe cases, aspiration [3,4]. POI may also lead to re-

admission and more expensive hospital stays costing over

$4000 ($4118 - $8785) [5]. The overall healthcare costs

from POI in the United States are estimated to be over

$1.46 billion annually [5].

It has been hypothesized that POI is caused by both an

inflammatory as well as a neural process. However, the

*Corresponding author.

B. F. KATZ ET AL. 273

process is multifactorial. The inflammatory response is

believed to be directly related to surgical injury of the

viscera triggering an immunologic response, and the

complex neural process involves the somatic, adrenergic,

and endogenous stress mediated pathways [6]. Opioid

use has been shown to exacerbate POI. The peripheral

µ-opioid receptor on the gastrointestinal tract has been

found to be a main contributory factor to POI when the

receptor is activated. By using opioid for post-surgical

pain control, the µ-receptor activation can lead to in-

creased colonic muscle tone and decreased peristalsis in

the GI tract [7].

Alvimopan is an oral selective antagonist to the pe-

ripheral µ-opioid receptor. Due to alvimopan’s large size,

zwitterionic form, and polarity, alvimopan does not cross

the blood-brain barrier, therefore allowing opioid central

analgesia [8]. Alvimopan has been shown to lower the

incidence of nasogastric tube insertion postoperatively,

and decrease POI and subsequently decrease hospital

stay by approximately one day [8,9]. The efficacy and

safety of the 12 mg oral dose has been well described in

the gastrointestinal and gynecologic surgery literature.

In the present study, our aim was to investigate the ef-

fect of alvimopan on POI in patients undergoing radical

cystectomy. Tolerance of a clear liquid diet and hospital

length of stay were used as surrogate markers for bowel

function. There are no documented studies on alvimo-

pan’s efficacy in urologic surgeries.

2. Material and Methods

Approval from the Institutional Review Board was ob-

tained to conduct a retrospective review of patients’ re-

cords from August 2009 until August 2011. The study

included sixteen patients who had undergone radical cys-

tectomy with ileal diversion. Exclusion criteria included

patients with chronic opioid use, previous colostomy or

ileostomy, or significant comorbidities which could cause

increased postoperative complications. The 16 patients

were consecutive cases performed by two different surgeons

in one institution; no patients were excluded in the trial.

All patients had their complete hospital medical re-

cords and preoperative evaluation reviewed. Patients’ de-

mographics included age, sex, race, BMI, procedure,

morbidities, need for nasogastric tube, days until clear li-

quids, length of stay, surgeon and use of alvimopan were

evaluated. For the purpose of this study, morbidities were

defined as any inpatient serious adverse events or read-

mission within 30 days postoperatively.

The cystectomy postoperative pathway in our patients

includes pain management, encouragement of early am-

bulation, incentive spirometry and advancing the patient

to a clear liquid diet once flatus is reported. Patients were

separated into two arms; alvimopan 12 mg and alvimo-

pan naïve. The alvimopan arm was given 12 mg orally 1

to 2 hours preoperatively in the preoperative holding area

and continued on alvimopan 12 mg twice daily until dis-

charge.

Statistical analysis was performed to examine the as-

sociation of alvimopan use with decreased time to dietary

advancement and decreased length of hospital stay. Uni-

variante analysis was obtained with P < 0.05. All statis-

tical tests were achieved using Stata (College Station,

TX), version 12.

3. Results

Sixteen consecutive patients were identified during the

allocated time period and all 16 patients were included in

our study. Of the 16 patients, 8 received alvimopan and 8

were alvimopan naïve. Mean patient age was 63.5 (range

46 to 78) and mean body mass index was 26 kg/m² (range

17 to 37). There were 4 females (25%) and all cases were

radical cystectomy with ileal noncontinent conduit. The

majority of the patients were Caucasian (56%), followed

by Asian (19%) and Hispanic (19%).

According to Table 1, the naïve arm was younger and

had a lower BMI as compared to the alvimopan group,

which had five patients over the age of 65 compared to

just one in the naïve group. The race and gender of the

two groups were similar. The alvimopan patients had

significantly less POI as compared to the alvimopan na-

ïve arm. Statistical significance was achieved with a P

value 0.0433 when comparing the two arms for advan-

cement to a clear liquid diet. The median time to a clear

liquid diet was 3 days versus 4.1 days in the alvimopan

group versus the naïve group, respectively. The hospital

course was shorter as well, with the alvimopan group

going home in a mean of 5.1 days versus 6.9 days

Table 1. Baseline patient demographics.

Demographics Naïve (n = 8) Alvimopan (n = 8)

Age (y)

Mean ± SD 60.4 ± 7.8 66.6 ± 10.1

≥65, n (%) 1 (13%) 5 (63%)

Race, n (%)

Caucasian 5 (63%) 4 (50%)

Asian 1 (13%) 2 (25%)

Hispanic 2 (25%) 1 (13%)

African American 0 1 (13%)

Gender, n (%)

Female 2 (25%) 2 (25%)

BMI*

Mean ± SD 24.9 ± 5.8 27.8 ± 3.6

≥30, n (%) 1 (13%) 2 (25%)

*BMI, body mass index; calculated as kg/m².

Open Access OJU

B. F. KATZ ET AL.

274

in the naïve group (Table 2). This variable also reached

statistical significance with a P value of 0.0451.

The readmission rate also favored the alvimopan group,

with two patients being readmitted for an infection and

bleeding duodenal ulcer (Clavien Classification II and I

respectively). The control group had four out of eight

patients readmitted within 30 days for 2 fevers and 2

abscess formation requiring intervention (Clavien Classi-

fication II and III respectively). It was expected that the

naïve group would have less complications due to their

younger age and lower BMI. None of the patients in ei-

ther group were readmitted for POI, small bowel ob-

struction or failure to thrive. Nasogastric tube insertion

was zero in both arms of the study.

4. Discussion

Post-operative ileus is a very expensive and frustrating

condition that affects many post-surgical patients. No

research on the use of alvimopan in preventing POI has

been reported in the urologic literature. This initial study

is the first report of alvimopan use in urologic surgery.

By starting 12 mg alvimopan prior to surgery and sub-

sequently prior to opioid use, our goal was to block the

µ-opioid receptors and diminish POI. Statistical signifi-

cance was achieved in our limited sample size for both

key factors in POI. The alvimopan group advanced their

diet more than 24 hours earlier in comparison to the al-

vimopan naïve group, and the alvimopan group had a

greater than one day or 26% shorter hospital length. We

showed a reduced risk of POI and subsequent decreased

hospital course length.

According to Bell and colleagues, a hospital day costs

an estimated $1300 to $1600 a day for a bowel resection

procedure. The $62.50 per dose of alvimopan if extrapo-

lated out to a five day hospital course would be equiva-

lent to around ten doses [5]. This cost, although not in-

significant, pales in comparison to one or more days in

the hospital. The Bell study goes on to state that the total

hospital savings was averaged to “$977 less for patients

who received alvimopan [5]. Our study had a greater

Table 2. Alvimopan versus control outcomes.

Naïve (n = 8) Alvimopan (n = 8)P Value

Days until PO order

Mean ± SD 4.1 ± 1.5 3 ± 0.9 0.0433

NGT placed, n

0 0

Hospital Length Days

Mean ± SD 6.9 ± 2.9 5.1 ± 1.2 0.0451

Readmission 30 Days

n (%) 4 (50%) 2 (25%)

than one and half day shorter hospital course and a much

sooner time to bowel recovery.

The use of alvimopan has been described in the gen-

eral surgery and gynecology literature for the prevention

of ileus [4,10]. According to Herzog et al., a dou-

ble-blind placebo controlled randomized trial using

alvimopan in female patients undergoing total abdominal

hysterectomy which did not resect bowel resulted in first

bowel movement 22 hours earlier and a safety profile

similar to placebo [4]. Our patients did not report any

allergies or adverse reactions; however, our study design

was not specifically designed to look at such results.

The naïve group had an estimated four days until the

patient’s diet was advanced on the report of flatus. Mul-

tiple other novel concepts have been reported to hasten

bowel recovery time. Erythromycin and early removal of

a nasogastric tube was not shown to improve time to

bowel sounds, flatus, passage of first bowel movement or

prevention of ileus [11,12]. Pruthi and colleagues de-

scribed a perioperative care plan involving, but not lim-

ited to, restricting bowel preparation, reducing incisional

length, and limiting narcotic analgesics. The study

showed a significant improvement from 1996-1997 of

mean time to clear liquid diet starting at 6.9 baseline and

improving to 2.0 days in the 2001-2002 current pathway

[13]. Perhaps the easiest and least expensive attempt to

shorten POI has been shown in gum chewing studies.

Kouba study and Choi study both found gum chewing to

improve time to flatus by 0.5 days [13,14]. Our study

found time to flatus and advancement of diet by more

than a day, and unlike the Kouba study, we found a sig-

nificant decrease in hospital length of stay. Choi did not

report data on length of hospital stay.

The alvimopan group had a slightly higher BMI and

age as compared to the controls. Increasing BMI and age

are “independent risk factors for the development of

postoperative paralytic ileus after radical cystectomy”

according to Svatek et al. [15]. They report POI in 10%

of “normal” weight patients (BMI 18.5 - 24.9 kg/m²) and

POI in 22.2% and 30.3% in BMI 30 - 34.9 kg/m² and

≥35 kg/m² respectively. Svatek et al. did not show a dif-

ference in POI when comparing EBL, need for blood

transfusion, operative time, the type of urinary diversion,

or use of epidural anesthesia [15]. Our alvimopan group

had a higher BMI (27.8 vs 24.9) and a higher age cohort

(66.6 vs. 60.4) as compared with the controls. One would

postulate that the alvimopan group should have a higher

rate of POI, but this was not the case. Statistical signifi-

cance was still obtained in our experimental arm.

This is one of the first reports of the use of alvimopan

in the urologic surgery literature to date to our knowl-

edge. There are limitations to this study. The limited

sample size poses a selection and sample bias. We were

able to show statistical significance; however, to deter-

Open Access OJU

B. F. KATZ ET AL.

Open Access OJU

275

mine the true impact of the results, the study should be

conducted on a much larger scale. The retrospective,

nonrandomized, single institution design implores us to

study this drug further. This initial report was intended to

show a preliminary trend towards decreasing the morbid-

ity of POI in radical cystectomy with ileal diversion by

using the drug alvimopan. Further and more detailed re-

search is evidently needed to decipher objectively the use

of alvimopan in urologic procedures.

5. Conclusion

To our knowledge we report one of the first uses of alvi-

mopan in reducing POI in the urological surgery litera-

ture. Our novel experience with using this drug is en-

couraging. Further research will ultimately determine if

standard use of alvimopan to decrease POI in radical

cystectomy with ileal diversion will be implemented.

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