Clinical trial NCT04387617
Conditions: Urinary Stone
Sponsor: Mayo Clinic
Start date: 2021-02-15; Completion date: 2022-01-31
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if CBD oil has any effect on decreasing postoperative pain control following ureteroscopy for urinary stone disease, and to determine if CBD oil has any effect in decreasing the amount of postoperative opioids (commonly used drug) used by patients after undergoing ureteroscopy for urinary stone disease.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Cannabidiol intervention 2: Placebo
Intervention descriptions: intervention 1: The product is a liquid formulation that will be prescribed at a dosage of 20 mg per day for a total of 3 days. intervention 2: The product is a liquid formulation placebo that will be prescribed at an equivalent volume as active drug for 3 days

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Effect of Cannabidiol Oil on 
Postoperative Pain After 
Ureteroscopy for Urinary 
Calculi 
 
 
NCT04387617 
 
 
10/16/2020 




Minimal Risk Protocol Template [IRB 10429.010] 
 
Effective: 9/20/2017 
 
 
 
 
 
 
 
 
Page 2 of 9 
 
medication compared to those randomized to the control condition also given opioids as a rescue medication. 
We will analyze number of use, the cumulative and per day usage of analgesic opioid medication. 
 
 
Background (Include relevant experience, gaps in current knowledge, preliminary data, etc.):   
 
Ureteroscopy is one of the mainstays of the surgical management of upper urinary tract calculi. In most 
cases, a ureteral stent is left postoperatively which unfortunately can lead to significant morbidity and 
discomfort for the patient.1 More than 80% of patients with a stent post-ureteroscopy report pain that interferes 
with their daily activities.1 It is common for providers, and typical protocol at our institution, to prescribe 
opioids post-operatively for pain control.  
In the past 15 years the number of opioid medication prescriptions in the United States has quadrupled. 
According to the CDC more than 47,600 people died from opioid overdoses in 2017, with one in three of those 
from prescription opioids.3 Currently, Arizona has one of the highest age-adjusted rates of drug overdose deaths 
in the country.3 Rates of death from overdose in Arizona was also shown to be increasing in recent years. Given 
the dramatic increase in opioid medication prescriptions in the United States, there has been a significant move 
towards finding alternative medications to manage patients’ pain.  
There are numerous biologically active compounds derived from Cannabis sativa, including the main 
phytocannabinoids tetrahydrocannabinol (THC) and cannabindiol (CBD)4,5. THC is the psychoactive 
cannabinoid derived from the flowers and leaves of the marijuana plant with intoxicating effects through the 
CB1 receptor. CBD is the main component of oil derived from the flowers and leaves of the hemp plant. It has a 
more complex mechanism of action than THC and has been shown to reduce inflammation, anxiety, and 
seizures4. Federal and state laws permit the growth and sale of hemp products, including CBD oil, provided the 
THC content does not exceed 0.3% of the dry weight5. Products with a THC content not exceeding 0.3% of the 
dry weight should not have the psychoactive effects known with THC and therefore theoretically have less risk 
of misuse or diversion and better safety profile than narcotics5.  
CBD oil has been purified as an oral solution as the drug Epidiolex. It received FDA approval for the 
treatment of rare seizure disorders in 2018 (FDA approval). Preclinical data have shown promise for the use in 
chronic pain with anti-inflammatory, antinociceptive and in the treatment of addiction5. It has not been studied 
in the postoperative or postureteroscopy setting. 
There is a significant amount of research studying the role of cannabinoids in chronic pain management, 
however very little research has been done on post-operative pain management with cannabinoids.6 Specifically 
within urology, cannabinoids have been shown to be effective in chronic pelvic pain syndrome/chronic 
prostatitis and help bladder dysfunction in multiple sclerosis patients.7,8 Cannabinoid receptors (CB1 and CB2) 
are present in the bladder, testis, prostate, and vas deferens.9 Endogenous cannabinoids interaction with these 
receptors is involved in the regulation of smooth muscle contractility.9 Alpha-receptor antagonists have been 
found to decrease ureteral stent discomfort by decreasing smooth muscle contractility in the ureter.10 
Theoretically, agonized cannabinoid receptors, if also present in the ureter, as they are in a significant portion of 
the urinary tract, could also decrease smooth muscle contractility and decrease stent related discomfort.  
Preclinical data have shown promise for the use in chronic pain with anti-inflammatory, antinociceptive and in 
the treatment of addiction5. There is a gap in the literature to date regarding the use of CBD oil in post-
ureteroscopy pain management, and post-surgery in general, but with increasing criticism on opioid prescribing 
practice, it is an arena that warrants investigation. Therefore, we propose a novel double blind randomized 
controlled study to compare pain control and safety with CBD oil and oxycodone (opioid) in the post-operative 
setting after ureteroscopy for urinary calculi. 




Minimal Risk Protocol Template [IRB 10429.010] 
 
Effective: 9/20/2017 
 
 
 
 
 
 
 
 
Page 4 of 9 
 
Randomization and allocation 
Patients will be randomized to one of two groups – trial medication or placebo.  Randomization 
schedule will be generated by the study statistician. Block randomization will be used to ensure temporal 
balance.  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, placebo controlled trial in which neither the patient nor the 
clinical team is aware of the group allocation.  The medications will be packaged inside a syringe.  The 
medication will be dispensed to the patient with a label that describes both medications, strengths, and 
administration schedule.  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 baseline blood work (CBC, BMP, and 
LFTs), imaging, 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 disguise the appropriate drug into an unlabeled generic container and dispense 
the prescription with appropriate instructions.   
• 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 syringe with the 
blinded medication with full administration instructions and safety leaflet.   
• 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 three days.  The patient will also fill out the Ureteric Stent Symptoms 
Questionnaire (USSQ) on postoperative days 1 and 3.   
• 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 bring all unused trial medication to the postoperative appointment, which 
will then be returned to the pharmacy staff.   
 
Rescue medication protocol 
• Patients will be prescribed an opioid pain medication per the typical protocol of the operating surgeon 
(12 tabs of oxycodone 5 mg). This can be taken at the patient’s discretion for increased pain. 
• All usage of opioids will be recorded by the patient on the daily data sheet. 


Minimal Risk Protocol Template [IRB 10429.010] 
 
Effective: 9/20/2017 
 
 
 
 
 
 
 
 
Page 5 of 9 
 
• 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, tamsulosin 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.  It is sensitive to treatment effects and data derived 
from it can be analyzed with standard parametric statistical techniques. Each day, patients will record their 
maximum and average pain scores.  Surveys to record the pain scores and rescue drug (oxycodone) 
administration will be handed to the patient on day of surgery as well as emailed out via an external REDCap 
database. We will combine the results from each study and compare the primary outcome between the two 
groups (i.e. control group and CBD oil group) in two ways: 1. overall, and 2. on a per day basis. 
Secondary outcomes 
• We will compare the number of use, the cumulative and per day usage of analgesic opioid medication 
between the two groups. 
• Usage of other medications, either self-administered, or prescribed will be compared 
• The rate of adverse clinical events defined as the rate of adverse drug reactions, rate of unscheduled 
phone calls, emergency room visits, hospital admissions, and clinic visits will be compared between the 
two groups. 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.  
• Comparison of ureteral stent symptom questionnaire (USSQ) scores on postoperative days 1 and 3. 
 
 
 
 








Minimal Risk Protocol Template [IRB 10429.010] 
 
Effective: 9/20/2017 
 
 
 
 
 
 
 
 
Page 9 of 9 
 
 
 
Data Analysis Plan:  
 
All the study data will be summarized by descriptive statistics. We anticipate the baseline characteristics 
between study groups will be comparable due to randomization. The point estimate and 95% confidence 
interval (CI) of the primary and secondary outcomes (pain score and USSQ scores) will be reported and 
compared by the two-sample t-test. If there is imbalance in the baseline characteristics between groups, we will 
fit a regression model to adjust for the possible confounding effect. The use of analgesic opioid medication 
(number of use, cumulative and per day usage) will be reported and compared by the two-sample t-test or Chi-
square test. All the adverse events observed during the study period will be reported and summarized by 
frequency count and percentages. 
 
 
References 
1. Joshi HB, Stainthorpe A, MacDonagh RP, et al. Indwelling ureteral stents: evaluation of symptoms, 
quality of life and utility. J Urol. 2003;169:1065-1069. 
2. Davis MA, Lin LA, Liu H, et al. Prescription opioid use among adults with mental health disorders in 
the United States. J Am Board Fam Med 2017; 30:407-417. 
3. https://www.cdc.gov/drugoverdose/data/index.html. Accessed December 17, 2019. 
4. Nickel JC, Medical marijuana for urologic chronic pelvic pain. Can Urol Assoc J 2018;12(6Suppl3). 
5. VanDolah HJ, Bauer BA, Mauck KF. Clinicians’ Guide to Cannabidiol and Hemp Oils. Mayo Clin Proc 
2019;94(9):1840-1851 
6. Whiting PF, Wolff RF, Desphande S, et al. Cannabinoids for medical use a systematic review and meta-
analysis. JAMA. 2015;313(24):2456-2473. 
7. Tripp DA, Nickel JC, Katz L, et al. A survey of cannabis (marijuana) use and self-reported benefit in 
men with chronic prostatitis/chronic pelvic pain syndrome. Can Urol Assoc J. 2014;8(11-12):e901-5.  
8. Brady CM, DasGupta R, Dalton C, et al. An open-label pilot study of cannabis-based extracts for 
bladder dysfunction in advanced multiple sclerosis. MultScler. 2004;10:425-33. 
9. Tyagi P, Tyagi V, yoshimura N, et al. Functional role of cannabinoid receptors in urinary bladder. 
Indian J Urol. 2010;26(1):26-35.  
10. Lamb AD, Vowler SL, Johnston R, et al. Meta-analysis showing the beneficial effect of α-blockers on 
ureteric stent discomfort. BJU Int. 2011;108(11)1894-902. 
11. Federal Drug Agency. Epidolex (cannabidiol) oral solution. June 2018