Double-blind, Placebo-controlled Randomized Controlled Trial of NSAID Prior to Ureteral Stent Removal in a Pediatric Population
Phase: NA
Conditions: Disorder of Urinary Stent, Ureteral Spasm, Ureteropelvic Junction Obstruction, Urolithiasis
Sponsor: University of Colorado, Denver

1
Study Title: 
Double-blind, Placebo-controlled Randomized Controlled Trial of NSAID Prior to Ureteral Stent Removal in a 
Pediatric Population
PI:
Jeffrey Campbell
Investigators: 
Alan Bielsky, Duncan Wilcox, Nicholas Cost, Vijay Vemulakonda, 
COMIRB #: 
14-0514
Revision Date: 3/23/2017
Protocol
Hypothesis and Specific Aims
We hypothesize that children who have a temporary, indwelling ureteral stent as part of 
care received during surgical treatment for either urolithiasis or ureteropelvic junction 
obstruction will experience a significantly smaller increase in post-operative pain if given 
a non-steroidal anti-inflammatory (NSAID) prior to removal of the ureteral stent when 
compared to placebo. We hypothesize that the incidence of severe post-stent removal 
pain is similar to an adult population. We aim to randomize patients who have an 
indwelling ureteral stent to either placebo or NSAID in a 1:1 ratio at least 15 minutes 
prior to the scheduled removal of the stent and compare pre-operative and post-
operative (24 hours) pain scores to examine our primary and secondary outcomes.
Background and Significance
Ureteral stents are commonly used after treatment of urolithiasis and after surgical 
repair of ureteropelvic junction obstruction.1 These stents can be very bothersome, 
affecting more than 80% of patients. This can result in increased flank and loin pain, 
dysuria, urinary frequency, even prompting unexpected emergency room visits.2,3 In 
some rare circumstances, the discomfort may be so great as to require intravenous 
narcotics, unplanned admission or even emergent procedures to remove or replace the 
offending ureteral stent. Medications such as α-blockers (e.g., tamsulosin) have been 
previously shown in multiple studies to ameliorate some of this effect while the stent is 
in situ.4,5 Despite its use, however, patients often continue to experience some 
discomfort and decreased quality of life.
Urologists have long commented on the anecdotal evidence that some patients 
experience severe, debilitating pain in the period following stent removal.6,7 While some 
have hypothesized that stent size and positioning may influence symptoms while the 
stent is in place, the physiologic mechanism behind pain after removal of the foreign 
body from the ureter is not well-understood. In vitro and in vivo studies have 
demonstrated ureteral spasm, which may cause the discomfort felt by patients. Spasm 
has been shown to be partially mediated by the generation of prostaglandins and hence 
blocked by cyclooxygenase (COX) inhibitors like NSAIDs. 8-10
Recently, a small double-blind placebo-controlled randomized controlled trial of a COX-
2 inhibitor (felt to have better selectivity in the ureter) given to adults prior to outpatient 
stent removal in the urology clinic was completed.11 22 patients were randomized, and 
demonstrated significant reductions in severe pain reported in the 24 hours after 
surgery (p < 0.01). 55% of patients in the placebo arm reported pain scores ≥ 7 out of 
10 versus zero patients in the intervention arm. Patients reporting severe pain in the 
placebo arm reported a mean 8.19 mg opioid medication use in the 24 hours after stent 
COMIRB
APPROVED
21-Apr-2017

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removal whereas only 1.67 mg was used in the COX-2 inhibitor group (p = 0.03). No 
adverse events were reported.
Prior to this study, no known interventions were used specifically to reduce “post-stent 
syndrome,” as some have termed the phenomenon.12 For pediatric patients with an 
indwelling ureteral stent, outpatient awake cystoscopy to remove a stent is not tolerated. 
As such, we typically bring patients to the operating room for a brief general anesthetic 
to allow for removal of a stent. At the termination of the procedure, intraurethral 2% 
viscous lidocaine is used (4 mg/kg or 0.2 mL/kg of 2% lidocaine up to maximum of 10 
mL).13 Virtually all patients receive a general anesthetic, and the use of NSAIDs pre-, 
intra-, or post-operatively is rare and inconsistently applied. These patients are 
instructed to take tamsulosin (an α-blocker) up to the day of their planned stent removal 
and then stop the medication. Afterwards, we generally instruct patients to alternate 
between acetaminophen and an NSAID (e.g., ibuprofen, a non-selective COX-1 and 
COX-2 inhibitor) as needed for any discomfort. No narcotics are typically prescribed. 
The incidence of “post-stent syndrome” in children is unknown.
Pain is difficult to objectively measure, particularly in children. Fortunately, there is a fair 
amount of research into various pain scales. The two we plan to use for this study 
include the Faces Pain Scale – Revised (FPS-R) or the visual analogue scale (VAS) 
depending on age. The FPS-R will be administered to children between 4 and 8 years 
of age, and the VAS will be given to patients between 9 and 18 years of age. Each of 
these scales has been validated and shown to be highly reproducible between 
individual patients. The FPS-R includes a series of faces indicating level of pain.14 
Standardized instructions are provided to the patient, and he or she is asked to indicate 
which face corresponds to his or her pain level. For older children (9 to 18 years of age), 
the VAS is a single line 100 mm long.15 The patient is asked to place a mark 
somewhere on the line, with the left end representing no pain and the right end 
representing maximal pain. The distance from the left side is measured with a ruler and 
rounded to the nearest centimeter (0-10). Given the wide range of ages, younger 
children have difficulty conceptualizing the VAS system. Fortunately, the two scales 
have been shown to be interchangeable.16
“Post-stent syndrome” remains real and its incidence in the pediatric population remains 
unknown. Our study will be the first to investigate the incidence of this problem in 
patients undergoing planned stent removal and also determine the effectiveness of 
prevention using a non-selective NSAID that is safe and commonly used in children 
(ibuprofen).
Preliminary Studies/Progress Report
No studies regarding prevention of post-stent removal pain have been conducted in 
children. Our study design is based on the double-blind placebo-controlled randomized 
controlled trial by Tadros et al published in 2013 that studied the phenomenon in 
adults.11 This study, as noted above, found a 55% incidence of severe pain in the 24 
hours after stent removal in patients that received a placebo. Severe pain was defined 
as a VAS score ≥ 7 at any point during the post-operative period.

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Research Methods
Outcome Measure(s)
Primary outcome: 
We hypothesize there will be at least a 75% reduction in post-operative severe pain 
(pain score ≥ 7) in patients receiving ibuprofen compared to those receiving placebo.
Secondary outcomes:
• Incidence of “significantly worsening” pain, defined as any increase ≥ 2 between 
the pre-operative and post-operative pain scale assessments for each patient
• Decreased incidence of “significantly worsening” pain, defined as any increase ≥ 2 
between the pre-operative and post-operative pain scale assessments in those 
receiving NSAID versus placebo
• Incidence of “severe” pain during post-operative period, defined as any absolute 
score ≥ 7 on the post-operative pain scale assessment in the placebo arm
• Smaller increase in from pre- to post-operative pain score in those receiving 
NSAID versus placebo
• Decreased opioid usage post-operatively recorded in equivalents to milligrams 
intravenous morphine in those receiving NSAID versus placebo
Description of Population to be Enrolled
We plan to enroll pediatric patients between the ages of 4 and 18 who have received 
and completed surgical care for either upper tract urolithiasis (nephrolithiasis or 
ureterolithiasis) or ureteropelvic junction obstruction requiring an indwelling ureteral 
stent who consent to randomization to receive either liquid ibuprofen or liquid placebo 
prior to stent removal. Inclusion criteria include: unilateral ureteral stent for treatment of 
urolithiasis or ureteropelvic junction obstruction with planned outpatient surgical 
procedure removal under light sedation or general anesthesia. Exclusion criteria 
include: patients undergoing other concomitant surgical procedures at time of ureteral 
stent removal, patients with bilateral stents, patients with complicated stent removal 
(encrustation requiring ureteroscopy and/or laser lithotripsy, proximal migration of 
ureteral stent), pregnant patients, patients with developmental delay who are unable to 
report pain scores, patients with contraindications to receive NSAIDs (documented or 
stated allergy to NSAIDs, chronic kidney disease, prior renal transplantation, history of 
nasal polyps, history of asthma).
Study Design and Research Methods
This will be a double-blind, placebo-controlled, prospective randomized controlled trial 
comparing a weight-based dose of liquid ibuprofen (10 mg/kg orally x 1 up to a 
maximum of 400 mg) to a similar-tasting and appearing liquid placebo of equal volume. 
Patients will be assessed for eligibility pre-operatively using the stated inclusion and 
exclusion criteria. Patients who are deemed eligible and agree to be enrolled will be 
consented for enrollment by a study investigator. A separate assent will be obtained for 

4
children between the ages of 7 and 12, while children between the ages of 13 and 17 
will be able to confirm assent on the main parental consent form. Those who are 
deemed ineligible or refuse enrollment will be excluded and reasons for exclusion 
recorded in the study database along with demographic data.
The patient will fill out a pain questionnaire (with the assistance of a study investigator), 
which included either the Faces Pain Scale – Revised (FPS-R) or the visual analogue 
scale (VAS) depending on age. The FPS-R will be administered to children between 4 
and 8 years of age, and the VAS will be given to patients between 9 and 18 years of 
age. Study investigators will record pain medications taken in previous 24 hours, record 
the last dose of tamsulosin, and review potential medication adverse effects. We will 
provide a similar pain questionnaire to be filled out in 24 hours (i.e., the day after 
surgery) with a addressed and stamped envelop to be returned to study investigators.
Patients who consent to enrollment will be randomized in a 1:1 ratio between liquid 
ibuprofen and placebo to be administered in the pre-operative area no fewer than 15 
minutes prior to going back to the operating room for induction of anesthesia and stent 
removal. Randomization to either liquid ibuprofen or similar looking and tasting liquid 
placebo of similar consistency will be performed by the research pharmacy, who will 
stratify by age, sex and indication for stent to ensure balance in the two arms of the 
study. Investigators and patients will be blinded to the randomization scheme and 
medication identity until study termination. When a patient is enrolled, an order will be 
placed in the computer for the study drug, the pharmacy will perform the randomization 
and determine which medication (ibuprofen versus placebo) to prepare in the proper 
dose. Study medication will be sent to the pre-operative area and administered by a 
nurse and documented. Study medication will only be given after completion of the pre-
operative questionnaire noted above.
Cystoscopy and stent removal will occur per standard of care under a short general 
anesthesia. Stent size, brand, and sidedness will be recorded. Cystoscopy will be 
performed with an age-appropriate sized scope to minimize discomfort per usual care. 
Scope size and configuration will be recorded. No opioid or NSAID medications will be 
given per usual practice. At the conclusion of the case, a weight-based dose of 2% 
viscous lidocaine (4 mg/kg up to maximum of 200 mg or 0.2 mL/kg up to maximum of  
10 mL) will be given intraurethrally per usual care. Post-operatively, we will instruct 
patients to take acetaminophen and/or ibuprofen in weight-based dosing per normal 
routine. Our instructions specify they should start with acetaminophen (10 mg/kg oral 
dose up to a maximum of 500 mg) three hours after study medication was administered 
pre-operatively and proceed to an appropriate dose of ibuprofen (10 mg/kg oral dose up 
to a maximum of 400 mg) three hours thereafter, alternating between the two. All post-
operative medications are to be taken only as needed, per usual practice, as long as 
there are no contraindications to their administration (acetaminophen: liver disease or 
liver failure; ibuprofen: documented or stated allergy to NSAIDs, chronic kidney disease, 
prior renal transplantation, history of nasal polyps, history of asthma).
Urology nurses typically call patients the day after surgery to review how a patient is 
doing and answer any questions. For study patients, we will use this call to also instruct 
parents on how to have the patient fill out the pain questionnaire and gather details on 

5
pain medication usage post-operatively, determine whether the patient required a visit 
to the emergency room or hospital admission, and screen for any adverse effects from 
study medication administration (see listing of potential adverse effects below). We will 
review the records of patients admitted to the hospital and will record additional 
medications and interventions. 
Description, Risks and Justification of Procedures and Data Collection Tools
Ibuprofen (a member of the NSAID class of medications) is commonly-used in children 
and is well-tolerated with minimal side effects. Its use is contraindicated in patients with 
kidney disease given its metabolism and clearance by the kidneys. Less commonly, it is 
contraindicated in patients with asthma, kidney transplantation, nasal polyps, or 
documented allergy to NSAIDs. Our exclusion criteria specifically forbid enrollment of 
patients in this study who have such contraindications. For those that are enrolled, we 
plan to warn patients and families regarding common and more rare side effects of 
ibuprofen. Common side effects include rash, nausea, dizziness, GI upset. Rare side 
effects include ringing in ears, itchiness, water retention, vomiting, diarrhea, mood 
changes, headache, blurred vision, double vision, bronchospasm, kidney failure. We will 
screen for these manifestations 24 hours after stent removal during the nursing call. 
Adverse events will be reported to Dr. Bielsky, who will act as independent safety 
monitor, to determine need for follow up actions and record such events prospectively 
as they occur. Dr. Bielsky, as safety monitor, may require access to pharmacy records 
to determine the nature of the medication administered according to the severity of any 
adverse events, which we do not anticipate. He will not participate in the data collection 
or analysis at the conclusion of the trial, maintaining a double-blind methodology.
Given ibuprofen is usually recommended to be taken as needed after stent removal in 
these patients, giving the medication pre-operatively poses little foreseeable risk to the 
patient. We view randomizing patients to ibuprofen versus placebo with resumption of 
standard of care after stent removal as a low-risk study with large potential benefit if we 
are able to demonstrate ability to prevent post-stent syndrome pain and measure its 
baseline incidence (in the placebo arm).
The data collection sheet provides a listing of data points we plan to gather for study 
patients. A minimum of demographic data will be collected on patients who are 
excluded or refuse to be included in the study. This will allow comparison of patients 
included to those excluded to examine for possible sources of bias. The data points 
provide all the necessary information to account for potential confounders and variables 
that may or may not contribute to the outcome measures we seek.
Potential Scientific Problems
We can identify several potential confounders in this study, including use of other pain 
medications or use of an α-blocker that may influence patient outcomes. We have 
designed this protocol to account for usage of these medications. Usage of different 
scopes for patients of different ages may account for some small differences in 
perceived discomfort around the time of stent removal. We will record the size of the 
scope used. Other variables that may influence the primary or secondary outcomes 

6
include stent size, stent duration, and indication for stent placement. These variables 
will all be recorded so as to evaluate their possible effect on outcomes, if any.
We have performed a power analysis as described below in an attempt to determine 
how many patients will be required to be randomized to answer our primary outcome. 
This power analysis is partly based on the Tadros et al randomized controlled study in 
adults. We have chosen a similar primary outcome, one we feel is suitable to our 
population and used the data from the adult population to derive the number of study 
participants we feel will provide adequate power. There is a chance we will not have 
enough power to adequately determine the primary outcome. Additionally, unlike in 
adults where stent removal is done awake, pediatric patients are given general 
anesthesia. This could attenuate the effect seen in adults. There is no accurate 
mechanism by which to predict whether such an effect might occur. Our study will make 
light of this, regardless of whether we are able to accept or reject our stated hypothesis.
Pain-related outcomes are very patient-specific and difficult to compare between 
patients, particularly raw or absolute scores. The Tadros et al study used an absolute 
cut-off of ≥ 7 to denote severe pain.11 This study can be criticized for using such an 
absolute cut-off as part of one of their intended outcomes because one patient’s “7” may 
not be the same as another patient’s “7.” Although comparing pre- and post-operative 
pain assessments for the same patient would offer greater internal validity, much larger 
sample sizes than are practical are necessary to detect even small changes. Other 
studies have shown that changes of even one point on a 10-point pain scale can be 
considered clinically significant, but poses the problem of requiring a large number of 
patients be randomized in order to detect that difference as statistically significant.17
Our study is designed to include children as young as 4 years old who can self-report 
pain. We felt in designing this study that including younger patients was important. As 
such, we must use two different pain scales, as they are designed and have been 
validated in different age groups. The results for both scales are reportable from 0 to 10.  
Comparison of the two scales demonstrate strong interscale correlation (r = 0.93, p < 
0.001).14 We feel the use of two different instruments will not be a significant source of 
bias. For comparison to the Tadros et al study, which did use absolute pain score ≥ 7 on 
the post-operative pain assessment as a study outcome, we will track incidence of 
“severe pain” and determine whether there is decreased incidence of this definition.11
Data Analysis Plan
Sample size estimation is based on primary outcome taking Tadros et al study results 
as reference without modification. A sample size of 20 patients from NSAID group and 
20 patients from placebo group achieve 80% power (β = 0.80) to detect a 75% 
reduction in the baseline 55% incidence of severe pain on the post-operative pain 
assessment (two-sided test, α = 0.05). 
At the conclusion of the study, study investigators will be unblinded as to medication 
assignment at time of randomization. Randomization factors such as age, sex will be 
examined between groups, should imbalance exist between groups, these factors will 
then be adjusted as covariate in regression models. In addition, potential confounders, 
such as α-blocker use will also be adjusted in the model. 

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The placebo and NSAID groups will first be compared using the two-sample t-test for 
continuous data, Chi-Square test or Fisher’s exact test for binomial data, and paired t-
test for FPS-R or VAS pain score data obtained pre- and post-operatively. Results will 
be considered significant at p < 0.05. The data will be used to determine results with 
respect to the above-stated primary and secondary outcomes. General linear 
regression, logistic regression may be used to analyze the data if necessary.
Summarize Knowledge to be Gained
From this study, we will learn the true incidence of post-stent removal pain experienced 
by pediatric patients and will learn whether NSAIDs given prior to ureteral stent removal 
can prevent such pain and discomfort from occurring. If there is a similarly strong effect 
by NSAIDs similar to that shown in adults, it will greatly reduce at least one aspect of 
the discomfort regarding stents in this vulnerable population. Such information will be 
invaluable in counseling future patients who require ureteral stents, and if our 
hypothesis is correct, improve care and quality of life for these patients.
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