Clinical trial NCT03584373
Conditions: Nephrolithiasis
Keywords: Pain Outcomes Ureteroscopy Percutaneous Nephrolithotomy Opioids
Sponsor: Montefiore Medical Center
Start date: 2018-07-27; Completion date: 2022-03-23
Enrollment: 119 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
There are two options for postoperative pain management: opioid and non-opioid analgesia. Pain outcomes will be compared in patients undergoing ureteroscopy and percutaneous nephrolithotomy by randomly administering opioid and non-opioid analgesia.

Detailed description:
Perioperative pain is often managed by opioids. However, post surgical pain management with opioids can often lead to long-term opioid use; additionally, opioids can cause unwanted side effects including respiratory depression that can lead to hypoxia and respiratory arrest, as well as nausea, vomiting, pruritus, ileus, and constipation. As an alternative to opioid perioperative pain management, non-opioid analgesia has been proven to be as effective as opioid management in acute pain. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and acetaminophen are often utilized as alternatives to opioid analgesia, and have an increased efficacy when combined. Both NSAIDS and acetaminophen have been proven to decrease opioid requirements and have minimized opiate-induced adverse events.

In this randomized clinical trial, pain outcomes after ureteroscopy and percutaneous nephrolithotomy will be investigated in patients who are treated with opioids versus a non-opioid regimen of ketorolac and acetaminophen. Percutaneous nephrolithotomy and ureteroscopy are minimally invasive surgical techniques to surgically remove kidney stones. This trial will seek to determine whether non-opioid therapy is noninferior to opioid therapy in the determination of pain intensity as measured by an 11-point numeric rating scale, in which 0 indicates no pain and 10 indicates the worst possible pain, one week after the surgery by telephone call.

Arms: arm 1: Ketorolac - Oral; 10 mg tablet: 1 tablet every 6 hours, or as needed. (20 tablets prescribed).

Acetaminophen - Oral; patient directed as needed. Not prescribed.

Ketorolac and Acetaminophen administered post surgery to compare pain outcomes to that of Percocet. arm 2: Percocet - Oral; 5 mg tablet: 1 tablet every 4-6 hours, or as needed. (10 tablets prescribed).

Percocet administered post surgery to compare pain outcomes to that of the non-opioid analgesia.
Interventions: intervention 1: Ketorolac Oral Tablet [Toradol] intervention 2: Acetaminophen intervention 3: Oxycodone Acetaminophen
Intervention descriptions: intervention 1: Ketorolac is a prescribed NSAID with strong analgesic activity. Ketorolac will be administered post surgery to compare pain outcomes to that of Percocet. intervention 2: Acetaminophen is an over-the counter pain medication that will be administered post surgery to compare pain outcomes to that of Percocet. intervention 3: Percocet is a prescribed opioid medication to manage pain. Percocet will be administered post surgery to compare pain outcomes to that of non-opioid analgesia.

Protocol documents:
Prot_SAP_000.pdf: 
IRB NUMBER: 2018-9031 
IRB APPROVAL DATE: 06/12/2020 
 
 
 
 
 
 
 
Title 
Pain outcomes of non-opioid analgesia after ureteroscopy or percutaneous nephrolithotomy for 
nephrolithiasis: a prospective randomized controlled trial. 
 
 
 
 
Protocol Version 3.0 05June2020 


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Title 
Pain outcomes of non-opioid analgesia after ureteroscopy or percutaneous nephrolithotomy for 
nephrolithiasis: a prospective randomized controlled trial. 
 
Purpose 
To compare postoperative pain outcomes of opioid vs non-opioid analgesia in patients 
undergoing ureteroscopy or percutaneous nephrolithotomy for treatment of 
nephrolithiasis. 
 
Principal Investigator: Dr. Kara Watts 
 
Study Location: Montefiore Medical Center (Moses, Weiler, and Hutchinson Metro campuses) 
 
Sponsor: none 
 
 
Background/Significance 
The United States is currently experiencing an epidemic of overdose deaths involving 
prescription opioids.[1] Along with mortality, the opioid epidemic has led to marked increases in 
morbidity and economic costs, as well as a rise in ED visits and substance-abuse treatment 
admissions. [1, 2] Perioperative pain is often managed by opioids [3-5]. Opioids bind to and 
modulate the effect of nociceptors in the central nervous system and peripheral tissues to cause 
analgesia.[6] Commonly prescribed opioids for acute pain include oxycodone, hydrocodone, and 
morphine. However, post surgical pain management with opioids can often lead to long-term 
opioid use.[7,8] This prolonged opioid use after surgical procedures has been seen both in 
patients who have existing opioid use and in those who are opioid-naive.[8] In addition, 
diversion of these opioids to others can occur when only a portion of the prescribed medication is 
taken; in fact, 67% of urologic patients had a surplus of opioid medication from the initial 
prescription in a survey of 210 patients who underwent surgery.[9] Besides dependence and 
addiction, opioid use can also cause unwanted side effects including respiratory depression that 
can lead to hypoxia and respiratory arrest, as well as nausea, vomiting, pruritus, ileus, and 
constipation.[6] As an alternative to opioid perioperative pain management, non-opioid analgesia 
has been proven to be as effective as opioid management in acute pain.[10] NSAIDs and 
acetaminophen are often utilized as alternatives to opioid analgesia, and have an increased 
efficacy when combined.[11] They both have been proven to decrease opioid requirements and 
have minimized opiate-induced adverse events.[12, 13] Non-opioid analgesics, including 
ketorolac (Toradol) and acetaminophen (Tylenol), are often used alone or in combination with 
opioids after major surgery.[14] Ketorolac (Toradol) is an NSAID with strong analgesic activity 
that works by inhibiting prostaglandin synthesis, and provides similar pain relief to that of 
opioids; the analgesic effect is slightly delayed but persists longer than that of opioids. It has 
been shown to decrease opioid requirements and has led to a decrease in opioid induced adverse 


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events, shorter hospital stays, and a faster return to normal gastrointestinal function than that of 
opioid use.[15] It does not alter gastric motility or adversely affect respiration, and it is not 
associated with abuse or addiction as opioids are.[15] Common side effects of ketorolac include 
prolonged bleeding times, GI ulceration and hemorrhage, nephropathies, and allergic 
reactions.[15] Acetaminophen (Tylenol) is a centrally acting analgesic that has been confirmed 
to be effective for acute pain, and has been shown to display opioid sparing effects.[6] A 
common side effect of acetaminophen is hepatotoxicity.[6] In this randomized clinical trial, we 
intend to investigate pain outcomes after ureteroscopy and percutaneous nephrolithotomy in 
patients who are treated with opioids versus a non-opioid regimen of Ketorolac and 
Acetaminophen. Percutaneous nephrolithotomy and ureteroscopy are minimally invasive 
surgical techniques to surgically remove kidney stones. This trial will seek to determine whether 
non-opioid therapy is noninferior to opioid therapy in the determination of pain intensity as 
measured by an 11-point numeric rating scale, in which 0 indicates no pain and 10 indicates the 
worst possible pain, one week after the surgery. 
 
 
Study Design and Population 
This will be an open label, prospective study of approximately 140 subjects undergoing either 
ureteroscopy or percutaneous nephrolithotomy. Depending on stone burden, location, and 
symptoms, patients will be counseled on the risks and benefits of both non-surgical and surgical 
stone management strategies including medical expulsive therapy, ureteroscopic stone 
extraction, ESWL, or percutaneous nephrolithotomy according to American Urological 
Association Guidelines. Patients who are eligible and choose to undergo ureteroscopy or 
percutaneous nephrolithotomy will then be asked if they would like to participate in the study 
and informed consent will be obtained. After consent is obtained, the electronic medical record 
will be checked to determine if the patient underwent a routine history and physical, as well if 
pre-operative imaging such as a plain abdominal film, renal/bladder sonogram, or non-contrast 
enhanced CT was obtained. Additionally, the chart will be reviewed to determine if there was a 
pre-operative urinalysis and culture. Patients will then be randomized to control (opioid 
analgesia) or non-opioid analgesia groups, and given this medication at discharge. Percocet 
(Oral, 5 mg tablet: 1 tablet every 4-6 hours, or as needed; 10 tablets prescribed) will be the 
medication for the opioid group, and Acetaminophen (Oral; patient directed as needed and not 
prescribed) and Ketorolac (Oral, 10 mg tablet: 1 tablet every 6 hours, or as needed; 20 tablets 
prescribed) will be the medications for the non-opioid group. The plan for randomization will be 
to use a random number generator to allot subjects to opioid and non-opioid groups. For all 
patients, we will record the age, sex, location of stone, stone burden (maximal diameter on CT 
scan), stone size, length of surgery, length of hospital stay, and pain medications administered 
after the surgery but prior to discharge. This is a non-inferiority trial in which primary outcomes 
are pain outcomes as measured by pain intensity levels one week after surgery when receiving 
non-opioid versus opioid analgesia. The patient will be asked, over telephone call, to complete a 
questionnaire rating their satisfaction with pain relief, current pain intensity level, worst and 
average pain intensity levels, and their belief of an acceptable pain intensity level since the 
surgical procedure; these will be measured on an 11-point ordinal scale.[16] The mean of these 


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values will be evaluated as the main analysis; secondary analysis will evaluate individual values. 
One week post-op, the patient will also be asked, via telephone call, about any adverse events 
experienced since the surgery, and how many medication pills they have left. As a secondary 
outcome, rates of constipation and rates of unused medications by the time of the phone-call one 
week after the surgery will be measured. Patients will be considered to complete the study after 
the follow up phone call, which occurs one week postoperatively. 
 
 
Inclusion Criteria 
1. Men and Women age>18 years old 
2. Presence of renal or ureteral stones suitable for ureteroscopy or percutaneous 
nephrolithotomy. 
3. Uncomplicated ureteroscopy or percutaneous nephrolithotomy 
 
Exclusion Criteria 
1. Pregnant/Breastfeeding/Possibly Pregnant Patients 
2. Pediatric Patients 
3. Sensitive or Allergic to Opioids, Ketorolac, or Acetaminophen 
4. Significant Renal Disease, or Creatinine>1.5 
5. Peptic Ulcer Disease 
6. Chronic Pain and recovering opiate use 
7. Inability to complete questionnaires. 
8. Non-mobile Patients 
9. Patients on methadone 
10. Known Asthma 
11. Bleeding Disorders 
 
Participant Recruitment 
Patients will be recruited in the course of regular care in the Urology clinic at Montefiore. Both 
subjects and controls will be recruited by physician referral. Patients diagnosed with ureteral or 
renal stones will be presented with surgical or non-surgical treatment options. If they choose 
ureteroscopy or percutaneous nephrolithotomy as their surgical treatment, the patient will be 
asked if they would like to participate in the study. Physicians will stress that participation is 
voluntary, that their decision will not impact the care that they receive, and that their patient 
privacy will always be protected. Informed consent will be obtained while the patient is in the 
clinic (Hutchinson clinic or pre-operative clinic) if they choose to participate. 
 
Cost 
The patient’s primary insurance will cover the cost of any surgical and post-surgical care as all 
procedures fall within the current standard of care. 
 
Informed Consent 
A written informed consent will be obtained (full text submitted to the institutional review 
board). Patients will be counseled that we are investigating pain outcomes based on the type of 


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analgesia utilized after undergoing ureteroscopy or percutaneous nephrolithotomy. Patients will 
be given all the available information regarding the risks and benefits of the type of analgesia, 
and they will be given the choice as to whether they would like to be enrolled in the study. 
Informed consent will be obtained by study personnel. All consent will be obtained in the 
Urology clinic (Hutchinson clinic or preoperative clinic) at the patient’s regularly scheduled 
appointment once a patient chooses to undergo ureteroscopy or percutaneous nephrolithotomy. 
 
Risk/Benefit 
The risks associated with participation in the study include the known risk factors of 
ureteroscopy and percutaneous nephrolithotomy, as well as that of opioid, Ketorolac, and 
Acetaminophen use. The known risk factors for ureteroscopy and percutaneous nephrolithotomy 
include infection, bleeding, ureteral damage or perforation, or injury to other organs. Common 
adverse events of opioids include confusion, vomiting, nausea, constipation, respiratory distress, 
urinary retention, and physical dependence. Possible risks of Ketorolac include peptic ulcers, 
gastrointestinal bleeding, cardiovascular thrombotic events, myocardial infarction, and volume 
depletion. A possible risks of acetaminophen is liver damage. Possible benefits to inclusion in 
the study include less opioid-induced side effects such as nausea, vomiting, constipation, and 
respiratory distress with similar pain relief. Broader benefits of the study include identifying 
whether non-opioid analgesia is as effective in treating postoperative pain as that of opioid 
analgesia. Perioperative outcomes may allow future patients to be spared side effects and the 
possibility of physical dependence that comes with opioid use. Additionally, the greater use of 
non-opioids post-operatively can be a modulating factor in reducing the current widespread 
opioid epidemic. 
 
Data Analysis 
Statistical Analysis 
Analysis will be based on the null hypothesis that there is no difference among opioid and 
nonopioid analgesia use in patients in regards to pain outcomes and adverse events. The alternate 
hypothesis is that there is a difference in regards to these 2 outcomes. This trial seeks to 
determine if non-opioid analgesia is non-inferior to opioid analgesia after ureteroscopy or 
percutaneous nephrolithotomy. Data will be analyzed using the Mann-Whitney U-Test. Patients 
will be analyzed via intention-to-treat analysis. 
 
Data Monitoring 
We will be following a Data Safety Monitoring Plan, with oversight by a Data Safety Monitoring 
Board (DSMB). The monitoring group will consist of three independent physicians in the 
Montefiore Urology department: Dr. Evan Kovac, Dr. Alexander Sankin and Dr. Beth 
Drzewiecki. The PI will give reports to the monitoring committee every six months for the 
duration of the trial on matters concerning enrollment and loss to follow up. This report will also 
include an analysis of protocol deviations, violations and adverse events. 


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Minutes of each DSMB meeting, along with recommendations, will be sent the PI. The 
investigator will also report to the DSMB immediately if there are any serious adverse events 
related to the study. 
 
We do not anticipate the trial will last long enough for many new scientific developments to 
occur in the interim, but the research assistant will monitor the literature (via pubmed) on 
nonopioid analgesia for postoperative pain. 
 
Determination of Sample Size 
The primary outcome in this study will be pain intensity as measured by the numeric rating scale 
at the postoperative visit. Other reported randomized trials measuring similar outcomes utilized a 
non-inferiority margin of 1.3. [17] Assuming a power of 80% with a 95% confidence interval, as 
well as a standard deviation of 2.6, each arm must contain 51 patients (total of 102) as calculated 
using PASS Software. Assuming a 36% attrition rate, we will recruit 140 patients (70 for the 
opioid group, 70 for the non-opioid group). 
 
Data Quality Control and Database Management 
All data will be kept on a secured, password-protected server that only the PI and research 
assistants will have access to. All data will be entered by the PI or research assistant. Data will be 
submitted in a de-identified manner (without name, MRN, zip code, or date of birth) to the 
DSMB to ensure quality of data entry on a monthly basis. Data collected for analysis will contain 
only de-identified patient information. The identifier log will only be able to be accessed by 
members of the study team. Once all patient data is collected and the study is over for three 
years, all patient identifiers will be removed from the database. 
References 
1. Volkow, N.D., et al., Medication-assisted therapies--tackling the opioid-overdose epidemic. 
N Engl J Med, 2014. 370(22): p. 2063-6. 
2. Leider, H.L., et al., Healthcare costs and nonadherence among chronic opioid users. Am J 
Manag Care, 2011. 17(1): p. 32-40. 
3. Kalso, E., et al., Opioids in chronic non-cancer pain: systematic review of efficacy and 
safety. Pain, 2004. 112(3): p. 372-80. 
4. Chou, R., et al., Clinical guidelines for the use of chronic opioid therapy in chronic 
noncancer pain. J Pain, 2009. 10(2): p. 113-30. 
5. Katz, J. and Z. Seltzer, Transition from acute to chronic postsurgical pain: risk factors and 
protective factors. Expert Rev Neurother, 2009. 9(5): p. 723-44. 
6. V, G. and C. C., Postoperative Pain Control. Clinics in Colon and Rectal Surgery., 2013. 
26(3): p. 191-196. 
7. Mudumbai, S.C., et al., Time-to-Cessation of Postoperative Opioids: A Population-Level 
Analysis of the Veterans Affairs Health Care System. Pain Med, 2016. 17(9): p. 1732-43. 
8. Sun, E.C., et al., Incidence of and Risk Factors for Chronic Opioid Use Among Opioid- 
Naive Patients in the Postoperative Period. JAMA Intern Med, 2016. 176(9): p. 1286- 93. 
IRB NUMBER: 2018-9031 
IRB APPROVAL DATE: 07/26/2018 


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9. Bates, C., et al., Overprescription of postoperative narcotics: a look at postoperative pain 
medication delivery, consumption and disposal in urological practice. J Urol, 2011. 
185(2): p. 551-5. 
10. Fujii, M.H., et al., Post-Discharge Opioid Prescribing and Use after Common Surgical 
Procedures. J Am Coll Surg, 2018. 
11. Ong, C.K., et al., Combining paracetamol (acetaminophen) with nonsteroidal 
antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute 
postoperative pain. Anesth Analg, 2010. 110(4): p. 1170-9. 
12. Chen, J.Y., et al., Opioid-sparing effects of ketorolac and its correlation with the recovery of 
postoperative bowel function in colorectal surgery patients: a prospective randomized 
double- blinded study. Clin J Pain, 2009. 25(6): p. 485-9. 
13. Gupta, A. and M. Bah, NSAIDs in the Treatment of Postoperative Pain. Curr Pain Headache 
Rep, 2016. 20(11): p. 62. 
14. Practice guidelines for acute pain management in the perioperative setting: an updated 
report by the American Society of Anesthesiologists Task Force on Acute Pain Management. 
Anesthesiology, 2012. 116(2): p. 248-73. 
15. Gillis, J.C. and R.N. Brogden, Ketorolac. A reappraisal of its pharmacodynamic and 
pharmacokinetic properties and therapeutic use in pain management. Drugs, 1997. 53(1): 
p. 139- 88. 
16. 
Helmerhorst, G.T.T., et al., Pain Relief After Operative Treatment of an Extremity 
Fracture: A Noninferiority Randomized Controlled Trial. J Bone Joint Surg Am, 2017. 
99(22): p. 1908-1915. 
17. 
Chang, A.K., et al., Effect of a Single Dose of Oral Opioid and Nonopioid Analgesics on 
Acute Extremity Pain in the Emergency Department: A Randomized Clinical Trial. Jama, 2017. 
318(17): p. 1661-1667.