Study of Ketorolac Versus Opioid for Pain After Endoscopy (SKOPE): A Double-blinded Randomized Control Trial Comparing Outpatient Analgesic Efficacy of NSAIDs and Opioids in Patients Undergoing Ureteroscopy for Kidney Stones
Phase: PHASE4
Conditions: Kidney Calculi, Ureteral Calculi
Sponsor: The Cleveland Clinic

 
 
 
 
 
 
 
 
 
 
Study of Ketorolac vs Opioid for Pain after Endoscopy (SKOPE): 
 
A double-blinded randomized control trial comparing outpatient analgesic 
efficacy of NSAIDs and opioids in patients undergoing ureteroscopy for 
kidney stones 
 
Document Date: November 29, 2018 

Study of Ketorolac vs Opioid for Pain after Endoscopy (SKOPE): A double-blinded randomized control 
trial comparing outpatient analgesic efficacy of NSAIDs and opioids in patients undergoing 
ureteroscopy for kidney stones. 
Study Coordinator: Naveen Kachroo, MD;  
Staff Investigator/Supervisor: Sri Sivalingam, MD 
Co-investigators: Manoj Monga, MD; Mark Noble, MD; Smita De, MD. 
Research team: Anna Faris, BA; Anna Zampini, MD; Donald Fedrigon, BS, Karen Stern, MD; Luay 
Alshara, MD; Heidi Digennaro, CNP; John Petrich, MS, R. Ph, Jianbo Li, PhD.  
 
INTRODUCTION, BACKGROUND AND SIGNIFICANCE 
 
The rate at which opioid pain medication is being prescribed in the United States has increased 
significantly within the last two decades.1,2 The societal cost of this trend includes an increase in rates of 
opioid abuse, addiction and fatal overdose.  These risks have motivated exploration of appropriate 
patient selection as well as alternative methods of pain control in clinical settings.  In this study, we aim 
to evaluate the efficacy and safety of an alternative (ketorolac) to opioids (oxycodone) for postoperative 
pain control in patients undergoing ureteroscopy (URS) for urinary stone disease. 
 
In the era of increased healthcare costs, efforts are being made to safely decrease the amount 
of time that patients spend in the hospital for a given procedure.  To this end, many procedures that 
entailed multi-day inpatient hospital stays are now treated as overnight stay, and sometimes even as 
outpatient procedures.  In the latter scenario, a significant burden of the required pain control falls to 
self-administration of oral pain medication by the patient after discharge.   As such, it is important for 
the clinician to ensure that the pain medication prescribed is: 1. effective, 2. well tolerated, and 3. of 
sufficient quantity to cover the expected post-operative pain period.  Getting the right mix of these 
three factors is critical in patient satisfaction.    
 
Currently, the American Urological Association (AUA) does not give any recommendation on the 
management of pain in post-URS patients.  Anecdotally, in the United States, the common practice is to 
prescribe a short course of opioid pain medication on discharge to patients undergoing URS for urinary 
stone disease, while few patients receive opioids in other parts of the world.  Whether this is due to 
decreased availability, or physician preference is unclear as the medical literature is lacking in this area.  
The particular opioid medication, quantity, and duration, and decision to prescribe adjunctive 
medication for stent pain and/or bladder spasms (eg. tamsulosin, oxybutynin, phenazopyridine etc) are 
usually a matter of physician preference. 
There is a preponderance of data for management of pain in acute renal colic but  data is lacking 
in the setting of post-URS pain.3  Pathophysiologic mechanisms for pain in acute renal colic and post-URS 
pain likely overlap significantly.  Irritation of the renal and ureteral tissues from the stone or 
instrumentation combined with ureteral inflammation, contraction and spasms are likely contributing 
factors.   

There is good evidence that NSAIDs offer superior pain relief compared to opioid medications in 
the acute renal colic setting.3–5 Wen et al. offer in vitro evidence that ketorolac decreases ureteral 
contractility which likely is a major contributor to pain in this setting.6  Pathan et al. conducted a large, 
double blind, randomized controlled trial to compare analgesic efficacy of NSAIDs, opioid and 
paracetamol (acetaminophen).  They found that NSAIDs produced better and more durable analgesia 
than opioids and had a better side effect profile.5 
Post-URS, many patients are left with a ureteral stent to keep the ureter patent during a 
postoperative period of ureteral inflammation and edema.  This stent unfortunately can itself be the 
cause of severe and bothersome symptoms, some of which are not treated effectively with opioids.  
Patients are given other medications (oxybutynin, phenazopyridine, tamsulosin) to help with this.  There 
is emerging data to suggest that stent-related pain may be more effectively dealt with using NSAIDs.7 
Clearly, there are several reasons to explore safe and effective alternatives to opioid 
medications in the setting of ureteroscopy.  Not only are we in a period of high rates of abuse and 
addiction, opioids can cause constipation, nausea, vomiting, and may not be effective in managing stent 
related symptoms.  To this end, we propose a double blind randomized controlled trial to compare pain 
control and safety with ketorolac (NSAID) and oxycodone (opioid) in the post-operative setting for 
patients undergoing ureteroscopy for treatment of urinary stones. 
 
STUDY DESIGN 
Methods 
 
This study is designed as a prospective, double-blind randomized controlled trial.  Two drugs will 
be administered in a blinded fashion and outcomes will be assessed with non-inferiority design. 
Sample size 
 
Based on previous data collected at our institution, the average pain score of patients 
undergoing ureteroscopy is 3.5 ± 2.5. derived from the following studies and also supported by the 
postoperative day 1 pain scores we have collected so far in the SKOPE trial (mean of 3.6 ± 2.0). .8–11 Kelly 
showed that when using a 100mm VAS pain scale (with 0mm indicating no pain, and 100mm indicating 
worst pain), the minimum clinically significant difference in pain rating was 14mm for patients with 
moderate pain (3.0 to 7.0 on VAS).12    
 
We performed a sample size calculation for the primary outcome of VAS pain rating.  Using the 
data in the available literature for a non-inferiority limit of 1.4, significance level α=0.05, 80% power, 
sample size calculation yields n=40 per group.13 
Inclusion criteria 
 
Patients who are diagnosed with kidney or ureteral stones confirmed on imaging (CT of the 
abdomen and pelvis) and who elect for definitive treatment via ureteroscopy at two sites within 
a tertiary care institution 
 
Age over 18 
 
Patients of either gender 
 
Patients of all ethnic backgrounds 

 
GFR >60 ml/min/1.73m2 (MDRD equation)  
 
Capable of giving informed consent 
 
Capable and willing to fulfill the requirements of the study 
Exclusion criteria 
 
Active or history of peptic ulcer disease, GI bleed/perforation 
 
History of coronary artery bypass graft surgery 
 
History of bleeding disorder 
 
GFR <60 ml/min/1.73m2 (MDRD equation) 
 
History of chronic pain  
 
Chronic use of opioid or other pain medication (>12 weeks) 
 
Chronic use of NSAIDs 
 
Known allergy to either ketorolac or oxycodone 
 
Known or suspected Pregnancy 
 
Inability to give informed consent or unable to meet requirements of the study for any reason 
 
Solitary kidney 
 
Patients taking anticoagulants or antiplatelet medication 
o Warfarin 
o Clopidogrel 
o Dabigatran (pradaxa) 
o Xarelto (rivaroxaban) 
o Eliquis (apixaban) 
 
RESEARCH PROCEDURES 
Trial Medications 
Two active treatments will be investigated: 
 
Ketorolac 10mg by mouth every six hours as needed for pain given for a maximum of 5 days (20 
capsules dispensed) 
 
Oxycodone 5mg by mouth every six hours as needed for pain given for a maximum of 5 days (20 
capsules dispensed) 
The medicinal products will be encapsulated, packaged and labeled so as to be unidentifiable by the 
patient.  Packaging will consist of a pill bottle labeled with the dosing and administration schedules for 
both drugs.  Drug safety sheets for both drugs will be provided as part of the package.   
Trial medication will be stored by the study pharmacy in a locked and labeled drawer for this 
particular study until they are dispensed to the patients.  Records of allocation and dispensation will be 
kept by the pharmacy. 
Rescue medication consisting of 3 doses of oxycodone 5mg will be dispensed along with the trial 
medication.   

A large prospective study performed by Forrest et al. demonstrated that the rate of serious adverse 
outcome with ketorolac use following major surgery was as follows: allergic reaction (0.12%), acute 
kidney injury (0.09%), and gastrointestinal bleeding (0.04%).14 
Common adverse drug reactions for ketorolac are abdominal pain, dyspepsia, heartburn, nausea, 
flatulence, dizziness, hypertension (1-10%).15 
It is commonly recommended to limit administration of ketorolac to 5 days. 
Common adverse drug reactions with oxycodone  are nausea, constipation, vomiting, headache, 
pruritus, dizziness, somnolence (>3%), and abdominal pain, anorexia, dyspepsia, anxiety, rash (<3%).16 
Identification and enrollment of patients (SEE CONSORT DIAGRAM BELOW) 
Patients will undergo standard consultation for treatment options for urinary stones.  Patients 
electing to undergo ureteroscopy for urinary stone disease will be identified and considered for 
enrollment during preoperative counseling in the urology clinic at two study sites.  A log will be taken of 
all patients assessed for inclusion in the study to inform the CONSORT diagram.  Those who satisfy the 
inclusion and exclusion criteria will then be approached for inclusion into the study.  Background, 
significance, risks, benefits, alternatives will be discussed in detail and all questions will be answered 
before signing consent form.  A copy of the research consent form with all of the above information will 
be given to the patients and the signed original consent form will be kept in the urology department as 
detailed in the Data Collection and Handling section. At the time of consent patients will also be asked if 
they would prefer to complete their postoperative surveys online. 
Randomization and allocation 
Patients will be randomized to one of two groups.  Randomization allocation by blocks will be 
created in conjunction with Dr. Jianbo Li in Quantitative Health Sciences and Dr. John Petrich in 
Investigational Drug Services.  Two separate randomization allocation lists will be created (one for each 
study site) and will be kept in a labeled, locked drawer in the study pharmacy at each study site.  Once 
patients have consented to being included in the study, they will be assigned a sequential study number, 
which will be passed onto the pharmacy study contact at the appropriate site to assign randomization 
allocation.  They will then dispense encapsulated trial medication based on that allocation.  
Blinding 
This is designed to be a double blinded study, in which neither the patient not the clinical team 
is aware of the group allocation.  The medications will be packaged inside an unlabeled capsule.  The 
medication will be dispensed to the patient with a label that describes both medications, strengths and 
administration schedules.  In this case, both drugs are administered with the same schedule (1 capsule 
by mouth every six hours as needed for pain).  The clinical team will be blinded to the allocation and will 
only receive the dispensed drug from the pharmacy contact and then bring it to the discharging nurse in 
the recovery room for inclusion with other discharge material. 
Preoperative and perioperative procedures 
 
Patient will undergo standard preoperative procedures including blood work (CBC, BMP), 
imaging (usually chest xray), and medical clearance as required. 

 
The procedure itself will be performed per standard practice of the surgeon, including choice of 
instruments, manner of fragmentation, and postoperative management of patient with regards 
to follow up appointments, stent placement and removal.   
Postoperative procedures 
 
The study pharmacy will package the appropriate drug into an unlabeled generic capsule and fill 
a pill bottle with appropriate instructions for both study drugs on the label.   
 
In the recovery room, the patient will fill out a 100mm pain visual analog scale sheet which will 
be kept in the study drawer in the urology department. 
 
The patient will then be given a packet of materials for data collection along with the pill bottle 
with the blinded medication with full administration instructions and safety leaflets.   
 
If the patient stated they would prefer to complete their surveys online then an email will be 
sent on postoperative day 1 with links to their surveys. Reminder emails with a link to that days 
survey will also be sent on days 2-5. Patients will still be sent home with physical copies of the 
surveys and patient identification cards in case of technical difficulties accessing the online 
surveys.  
 
The patient will fill out the data sheets for pain scale, trial, rescue and other medication usage, 
and adverse events on a daily basis for five days.  The patient will also fill out the Ureteric Stent 
Symptoms Questionnaire (USSQ) on postoperative days 1 and 5.  
 
A phone call will be made to the patient on postoperative day 1 to assist with study related 
questions. Patients completing their surveys online will still be contacted via phone to assist 
with research related questions. 
 
If physical surveys completed the patient will then mail the data sheets to the urology 
department using a provided stamped-addressed envelope or hand in the data sheets at their 
postoperative appointment. 
 
The patient will be required to being all unused medication to the postoperative appointment, 
which will then be returned to the pharmacy staff.   
 
Postoperative visit will be scheduled for postoperative day 5 for removal of stent.   
 
Rescue medication protocol 
 
Patients will be provided with three doses of rescue medication (oxycodone 5mg every six hours 
as needed for pain) alongside their trial medication.  This can be taken at the patient’s discretion 
for VAS pain scores >4. 
 
All usage of rescue medication will be recorded by the patient on the daily data sheet. 
 
Given that the presence of the stent itself can be a significant factor in the pain and discomfort 
for patients undergoing URS, we will also allow for patients to be prescribed oxybutynin and/or 
phenazopyridine at the discretion of the clinical team.  These two medications, along with 
tamsulosin (given to patients routinely following URS) are very commonly used to mitigate stent 
pain in post-URS patients.  Use of all adjunct medications will be recorded by the patient on the 
daily data sheet. 
Emergency situation procedures 
Participants will be given a patient card, which will have the study title, investigational 
medication product details, participant identification number and contact details for clinical study team 

members for business and after hours.  If a patient has pain which is not controlled despite use of trial 
and rescue medications, then patient will have the option to call into the surgeon’s office (during 
business hours) or the after-hours call number, which is usually directed to the resident on call.  The 
patient will give the trial information on the patient card to the resident returning the call. Treatment 
plan at that point will be developed by the resident in conjunction with on call staff as per usual 
protocol.  This may include medications prescribed over the phone, scheduling office visits as well as 
emergency room visits.  . 
Subject withdrawal 
 
Participants will remain on the trial unless they choose to withdraw or they no longer meet the 
inclusion and exclusion criteria.   
Outcome measures 
The primary outcome measure will be the pain score given by patients on the 100mm continuous 
visual analog scale (VAS).  The VAS is an easy to use instrument for evaluating pain severity.  It provides 
reproducible results that do not differ with age, gender or cause of pain.17,18 It is sensitive to treatment 
effects and data derived from it can be analyzed with standard parametric statistical techniques.12,17,19 
Each day, patients will record their maximum and average pain scores.  We will compare this between 
the two groups in two ways: 1. overall, and 2. on a per day basis. 
Secondary outcomes 
 
We will compare the cumulative and per day usage of analgesic medication between the two 
groups. 
 
Usage of other medications, either self-administered, or prescribed will be compared 
 
Requirement of rescue medication will be compared between the two groups 
 
Adverse events will be compared between the two groups 
o Rate of adverse drug reactions 
o Rate of unscheduled phone calls, emergency room visits, hospital admissions, and clinic 
visits 
 
Comparison of USSQ scores on postoperative days 1 and 5. 
Data analysis 
Data analysis with be performed using R 3.3.2 and RStudio 1.0.136.  The main outcome of pain 
score will be analyzed using Student t test.  Numerical outcomes will be analyzed using Student t test 
while categorical variables will be analyzed using chi square test. 
Feasibility, cost and time frame 
Based on query of prospectively collected stone database, we perform 320 URS for urinary 
stone disease.  Based on a conservative 50% recruitment rate, we anticipate that we will be able to 
accrue 166 patients in approximately 12 months.  
As this is considered an investigator-initiated study, it falls under tier 1 pricing for the 
Investigational Drug Service at CCF.  This entails a $1500 start-up cost, $60 monthly maintenance cost, 
$40/patient dispensation cost, and medication cost of approximately $54.11 /100 tablets of oxycodone 

5mg and $215.71/100 tablets of ketorolac 10mg.  For 166 patients and a proposed 12 month schedule, 
total cost for this service would be approximately $13608.48. 
Research coordinator support will also be required to assist with answering questions, obtaining 
consent and handling of data sheets.  At an estimated $27/hour and estimated 414 hours, this is an 
estimated cost of $11178. 
An additional estimated $200 will be required for printing materials related to the study, 
packaging, mailing costs. 
Strengths 
There is limited data which directly compares NSAIDs to opioid medication in the post-
ureteroscopy setting as a means of pain control.  A prospective randomized controlled trial would give 
us excellent level A evidence as to whether ketorolac is a reasonable alternative to offer to these 
patients.  Double blinded design would decrease inherent biases of non-blinded studies.  Power analysis 
suggests a relatively small sample size in each group which means that this would feasible to do within a 
reasonable time span.  
Limitations 
Pain scores and medication usage are self-reported, with inherent limitations of not knowing if 
patients are recording medication usage accurately and whether they are taking other drugs for 
analgesia. 
Adverse events and reporting 
1. Collection of adverse events will be done by a combination of patient self-report on data sheets 
and data gathering from electronic medical record to search for evidence of phone calls, 
emergency room visits, hospital admissions, clinic visit notes. 
2. Reporting to IRB - The principal investigator or other member of the research team will report 
any adverse events to the IRB within 7 days of awareness.  Participant safety will be protected 
by standard of care for the surgical procedure which includes standard postoperative follow up 
visit usually within 8 weeks of the procedure. 
CONSENT 
Patients who select ureteroscopy for treatment of their renal calculi will be recruited to the study by 
Drs. Monga, Noble or Sivalingam , study team members or research coordinators during their initial 
clinic visit.  These staff surgeons will first determine if they are interested in participating in research, 
and upon agreement, the study coordinator will introduce the study details and initiate the consent 
interview at the time of the clinic visit in a private clinic room.   
The consent form will be thoroughly discussed, including the research procedures, risks, benefits 
and alternatives.  Voluntary agreement to participate in the study and signing of the consent will be 
conducted in the presence of the study coordinator either at the time of the initial clinic visit or at the 
pre-operative clinic appointment. As an option, the patient may be given the consent form to review for 
a few days at home, with plans to contact the study coordinator with questions.  During this time, the 
study coordinator will conduct a follow-up phone call to ensure the patient has received adequate 

counseling on the study.   Initiation of the consent process at the time of their first clinic visit will be 
noted in their electronic medical record. The patient will receive a signed copy of consent form and the 
original signed consent form will be kept in a study folder kept in a locked cabinet in the urology 
department. 
 

 
patients withurianry 
stone electing to 
undergo 
ureteroscopy
assessed for eligibility 
during standard 
clinical consultation
consented
randomized
ketorolac
undergoes 
ureteroscopy
fills out pain VAS in 
recovery room
fills out daily pain 
VAS and medication 
administration self-
reporting form for 5 
days
oxycodone
undergoes 
ureteroscopy
fills out pain VAS in 
recovery room
fills out daily pain 
VAS and medication 
administration self-
reporting form for 5 
days

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