Clinical trial NCT03176316
Conditions: Ileus Fusion of Spine
Keywords: ileus fusion of spine
Sponsor: Loyola University
Start date: 2017-09-20; Completion date: 2020-02-20
Enrollment: 53 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Postoperative ileus and opioid induced constipation are well-known post-operative complications. Previously, research has shown that using peripherally acting opioid antagonists can help alleviate the condition. There has not been a prospective study to investigate whether use of peripherally acting opioid antagonists are effective in preventing post-operative ileus in patients having spinal fusion surgeries.

Detailed description:
Post operative ileus is a well-known complication following spinal fusion surgery. There has been some literature to demonstrate the safety and efficacy of oral naloxone to decrease the time to bowel movements after gastrointestinal surgery, to date, there have been no studies within the spine fusion literature to investigate oral naloxone's effects on the time to bowel movements.

The aim of the present study is to use the previously established protocols and doses established in the gastrointestinal literature to see whether oral naloxone can decrease the time to first bowel movements.

Arms: arm 1: 1 mg/ml oral solution administered enterally every eight hours for 48 hours
Interventions: intervention 1: Naloxone
Intervention descriptions: intervention 1: Naloxone is an opioid antagonist (i.e., a medication used to reverse or reduce the effects of opioids)

Protocol documents:
Prot_SAP_000.pdf: 
NCT03176316    
Effect of Oral Naloxone in Relieving Post-operative Ileus in Patients Undergoing Spinal Fusion 
 
Protocol Date: 9/3/2020 
 
NCT03176316    
 
 


NCT03176316    
Effect of Oral Naloxone in Relieving Post-operative Ileus in Patients Undergoing Spinal Fusion 
 
Protocol Title: Preventing post-op ileus with oral naloxone 
Protocol Version: 2 
Protocol Date: 9/3/2020 
Principal Investigator: Dr. Russell Nockels 
Research Team: Kevin Swong MD, Michael Wemhoff MD, Ryan Hofler MD, Miri Kim MD, PhD, 
Daphne Li MD, Daniel Heiferman MD, G. Alexander Jones MD, Michael Schneck MD, Stephanie 
Bennett, PharmD, Joshua Simon MD, John Tsiang MD, Rachyl Shanker BS. 
 
 
I. Abstract  
Postoperative ileus and opioid induced constipation are well-known post-operative 
complications. Previously, research has shown that using peripherally acting opioid antagonists 
can help alleviate the condition.1 There has not been a prospective study to investigate whether 
use of peripherally acting opioid antagonists are effective in preventing post-operative ileus in 
patients having spinal fusion surgeries. 
   
II. Background and Significance/Preliminary Studies  
Post-operative ileus is a well-recognized entity and can significantly prolong a patients’ length 
of stay in the hospital.2 Anterior surgical approaches and duration of surgery for spinal fusion 
have been shown to increase the incidence of post-operative ileus with no successful 
intervention identified that reduces the incidence of ileus.2 
 
Naloxone is an opioid antagonist which is FDA approved as an intravenous agent for the 
reversal of adverse effects associated with synthetic and naturally occurring opioid agonists.3 
Enteral administration of naloxone has been investigated for the reversal of opioid induced 
constipation.4-7 Naloxone administered via the enteral route has been shown to antagonize the 
effect of opioid medications peripherally without affecting pain control.4-7 There was a 
significant increase in bowel movements and reduction in laxative use without a significant 
impact on pain control.4-7 
 
I. Study Aims  
The current study will assess the safety and efficacy of an enteral formulation of the opioid 
antagonist naloxone in prevention of post-operative ileus and opioid induced constipation. 
 
I. Administrative Organization 
This is a single center study to be completed at Loyola University Medical Center.  Participants 
may be located on a number of different in-patient units including Neurosciences Intensive 
Care Unit (2W), Surgical Intensive Care Unit (4N/S/WICU), Cardiac Care Unit (3HTU), Progressive 
Care unit (2N/PCU), and medical-surgical wards (2E or 4T). 
 
I. Study Design 


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This is a prospective, historically controlled observational trial of enteral naloxone use in 
patients admitted for spinal fusion surgery and receiving opioids for pain management. 
Primary outcome: Time to first bowel movement (hours) 
Secondary outcomes:  
• Hospital length of stay 
• Incidence of post-operative ileus. Post-operative ileus will be diagnosed through a 
combination of clinical exam and radiographic (X-ray) findings 
• incidence of post-operative constipation (defined as 3 days without a bowel movement)  
• average numerical  pain scale (Adult Nonverbal Pain scale or Visual Analog Scale) on 
post-operative days 0, 1, 2, and 3  
• average daily opioid requirement on post-operative days 0, 1, 2 and 3 (morphine 
equivalents) 
• number of naloxone doses administered 
• average number of daily bowel movements,  
• number of medication escalations required (defined as use of an as needed laxative 
medication or addition of a new order for a laxative medication) 
• Incidence of adverse effects 
• Incidence of study drug discontinuation 
 
II. 
Study Procedures 
Inclusion/Exclusion Criteria 
Patients will be included if they are having an in-patient spinal fusion procedure, are 18 years or 
older, post and post-operative pain control plan includes opioid medications.  Patients will be 
excluded if they are pregnant, nursing, under the age of 18, have an allergy to naloxone or its 
related products, or if they are having an outpatient procedure. 
 
Study recruitment 
Recruitment will take place prior to surgery.  Initial contact with prospective participants will 
occur in the pre-operative clinic visit which occurs 1 – 12 weeks prior to surgery.  A member of 
the study team will provide the patient with a copy of the informed consent document to 
review and take home.  The patient will be given an opportunity to ask any questions they may 
have about the study.  Patients will then be approached on the day of surgery to sign the 
consent form when surgical consent is obtained. Consent will be obtained by one of the 
neurosurgery residents involved with the study. 
 
Screening procedures 
Patients will be screened at the pre-operative clinic visit based on the inclusion and exclusion 
criteria. 
 
Historical controls will be identified by a report of patients undergoing spinal fusion procedures 


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identified via ICD9 codes in the previous 3 years. ICD-9 codes include a short fusion surgery 
(81.06, 81.62) with 3 or fewer vertebral body segments, long fusion surgery (81.63, 81.64), 
more than 4 vertebral segments, anterior approaches (81.06) and posterior approaches (81.07) 
in the thoracic and lumbar spine.  The historical controls will be matched to active participants 
based on age, gender, Charleston co-morbidity index, complexity of surgery, and duration of 
surgery.   
 
Study Intervention 
Active study agents: Naloxone 
Blinding/labeling/preparation of agents: No blinding is required in this study.  The study drug 
will be prepared, unit dose labelled, and patient labelled according to institutional protocols.  
Storage: Secured at room temperature in the central pharmacy then dispensed as a patient 
specific supply and stored at room temperature the automated dispensing cabinet.  No more 
than a 24 hour supply will be dispensed at any given time. 
Administration: 4 mg of a 1 mg/ml oral solution administered enterally (oral, nasogastric, 
orogastric, gastrostomy, or jejunostomy) every 8 hours for 48 hours 
 
Toxicities and guidelines for adjustments 
Potential adverse effects associated with the use of enteral naloxone have been associated with 
abrupt reversal of opioid activity with the most uncomfortable or dangerous of these being 
antagonism of central opioid activity and loss of pain control.  Additional adverse effects 
include nausea, vomiting, diarrhea, hypertension, tachycardia, diaphoresis, and mental status 
changes.  Patients will be monitored for adverse effects via routine vital signs, pain score, and 
neurological assessment every 1 – 4 hours and evaluation for emesis, bowel movements, and 
diaphoresis.  Study drug will be discontinued in patients who meet any three of six criteria 
within 1 hour of study drug administration: 
1. Heart rate increases > 20 beats per minute for > 5 minutes  
2. Respiratory rate increases to > 20 breaths per minute 
3. Diaphoresis 
4. Pain score increases by > 50% 
5. Emesis 
6. Diarrhea (defined as > 1 large, liquid bowel movement within 1 hour) 
Study Assessments and Activities 
All patients will undergo the scheduled operation per routine. Post operatively, all usual 
medications for pain control and bowel movements will be ordered according to institutionally 
approved and reviewed post-operative order sets. All home medications will also be reconciled 
and restarted as deemed clinically appropriate by the interdisciplinary care team. Oral naloxone 
4 mg enterally every 8 hours will be initiated on post-operative day 1 at 0900. Study drug will 
be discontinued as described in the study protocol, after 48 hours, or upon discharge whichever 
is sooner. 
 
III. Safety Monitoring Plan 


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Definition of adverse events, serious adverse events 
Adverse event: Any reported or observed event that is not part of the usual post-operative 
clinical course. 
Serious adverse event: Any event that requires discontinuation of the study drug 
Any serious adverse events will be reported immediately to the IRB.  All identified adverse 
events will be reported in the final analysis of this study.  Upon completion of data collection, 
all adverse events will be evaluated by study personnel and adjudicated for their relation to 
study drug. 
 
What procedures will be used to monitor subject safety 
Patients will be monitored for adverse effects via routine vital signs, pain, and neurological 
assessment every 1 – 4 hours and evaluation for emesis, bowel movements, and diaphoresis.  
These evaluations do not represent an additional burden to the patient since they are a part of 
routine post-operative care. 
 
Protected health information and data security 
All protected health information associated with the historical cohort will be stored in a 
password protected Microsoft Excel file on the SSOM Research secured drive.  De-identified 
patient information will be entered into a RedCap database for data collection.  All signed 
consent forms will be collected and securely kept in the patients’ medical record through EPIC.  
 
I. Analysis Plan 
Power Analysis 
Power estimates for this study were based on prior work by Lee et al.8  In their study, patients 
were randomly assigned to receive morphine with naloxone or morphine without naloxone.  
They found that those who received naloxone had a shorter time to first postoperative passage 
of flatus (M = 51.9hr, SD = 16.6hr) versus control (M = 87.0hr, SD = 19.5hr).  Similarly, the 
authors found that time to first feces was faster in the naloxone cohort (M = 95.3hr, SD = 
25.0hr) than control group (M = 132.9hr, SD = 29.4hr).  However, their study duration was 
exceedingly long with a maximum duration of approximately 160-180 hours.  One goal of this 
study is to estimate the effect of naloxone on time to first feces within the first 120 hours (5 
days) following treatment.  In this study, patients who require a second intervention or who do 
not experience flatus or feces by Day 5 will be censored. 
 
The null hypothesis is that the bowel movement (BM) rate is identical in the two groups 
(control and naloxone).  Power is computed to reject this null hypothesis.  Computation of 
power is based on a hazard ratio of 1.508.  Specifically, it assumes instantaneous BM rates of 
0.160 for the control group versus 0.241 for the naloxone group. This is equivalent to a median 
time of no BM of 4.34 days for the control group versus 2.879 days for the naloxone group.  At 
5 days, it is hypothesized that 45% of the control cohort versus 30% of the naloxone cohort will 
require a second intervention because they have not experienced a BM. 
 
With a total of 150 patients entered into the naloxone group and a total of 150 historical 
controls, the study will have power of 80.1% to yield a statistically significant result.  The 


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criterion for significance (alpha) is set at 0.050, and the test will be 2-tailed meaning an effect in 
either direction will be interpreted. 
 
Analysis Plan 
Two different approaches will be used for the primary aim.  First, a paired t-test will be used to 
estimate the mean difference in hours to first feces between the active cohort and historical 
control cohort.  For this analysis, the origin of time for both groups is start of surgery.  If 
necessary, a Wilcoxon signed ranks test will be used to compare the two distributions.   
 
A second approach will compare the instantaneous rates of bowel movements between the 
active and control cohorts using a Frailty survival model that allows for clustering of patients 
within their matched strata.  In this analysis, control patients who required treatment for ileus 
will be censored at the time of such treatment, and active patients who require an additional 
treatment beyond receipt of naloxone will be censored at the time of such treatment.  All 
patients who do not achieve BM by 120 hours will also be censored.  Hours to first feces for 
both groups will be start of surgery.  While we assume there is no immortal time bias between 
start of surgery and receipt of naloxone for the active cohort, a conditional landmark method 
may be used to account for the amount of hours between surgery and receipt of naloxone.9   
The proportional hazards assumption for all predictors will be tested using Martingale residuals 
as described by Lin, Wei, and Ying.10 
 
Regarding the secondary aims, a linear mixed effects model will be used to compare LOS 
between the two groups.  A generalized linear mixed effects model will be used to compare the 
two groups on all other secondary outcomes.  In these models, random intercepts will be 
allowed for each case-control matched strata in order to account for the correlation between 
cases and controls based on age, gender, Charleston co-morbidity index, and operation time 
under anesthesia. 
 
 
References 
 
1. 
McNicol E, Boyce DB, Schumann R, Carr D. Efficacy and safety of mu-opioid antagonists 
in the treatment of opioid-induced bowel dysfunction: systematic review and meta-analysis of 
randomized controlled trials. Pain Med 2008;9:634-59. 
2. 
Fineberg SJ, Nandyala SV, Kurd MF, et al. Incidence and risk factors for postoperative 
ileus following anterior, posterior, and circumferential lumbar fusion. The spine journal : official 
journal of the North American Spine Society 2014;14:1680-5. 
3. 
Naloxone [Package Insert]. Lake Forest, IL:Hospira, Inc.; 2007. 
4. 
Arpino PA, Thompson BT. Safety of enteral naloxone for the reversal of opiate-induced 
constipation in the intensive care unit. Journal of clinical pharmacy and therapeutics 
2009;34:171-5. 
5. 
Meissner W, Leyendecker P, Mueller-Lissner S, et al. A randomised controlled trial with 
prolonged-release oral oxycodone and naloxone to prevent and reverse opioid-induced 
constipation. Eur J Pain 2009;13:56-64. 


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6. 
Meissner W, Schmidt U, Hartmann M, Kath R, Reinhart K. Oral naloxone reverses opioid-
associated constipation. Pain 2000;84:105-9. 
7. 
Sykes NP. An investigation of the ability of oral naloxone to correct opioid-related 
constipation in patients with advanced cancer. Palliative medicine 1996;10:135-44. 
8. 
Lee J, Shim JY, Choi JH, et al. Epidural naloxone reduces intestinal hypomotility but not 
analgesia of epidural morphine. Canadian journal of anaesthesia = Journal canadien 
d'anesthesie 2001;48:54-8. 
9. 
Putter H. Landmarking. Handbook of survival analysis. Boca Raton, FL: CRC Press; 2014. 
10. 
Lin DY,Wei, LJ; Ying, Z. Checking the Cox model with cumulative sums of martingale-
based residuals. Biometrika 1993;80:557-72.