Intra-nasal Ketorolac for Acute Ureteral Stent-associated Pain Following Ureteroscopy for Stone Disease

Study Overview
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Brief Summary
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Objective: To improve quality-of-life and health care delivery to patients receiving ureteral stents. Specific Aims: Evaluate the feasibility, practicality, and qualitative outcomes of utilizing intra-nasal ketorolac in patients with indwelling ureteral stents (Phase I), followed by a randomized trial comparing two non-steroidal anti-inflammatory drugs, intra-nasal Ketorolac versus oral Diclofenac. Hypotheses: Due to its favorable pharmacokinetics in relieving acute pain, investigators expect improved pain scores and a lower rate of unplanned clinical encounters in patients receiving intra-nasal ketorolac compared to those taking oral diclofenac following ureteroscopic surgery for urolithiasis. Study Rationale: Following ureteroscopic management of urolithiasis, patient with indwelling ureter stents have higher levels of discomfort compared to those without a ureter stent. Prior studies showed that intramuscular Ketorolac at time of ureter stent removal decreased the incidence of unplanned clinical encounters. Furthermore, onset of analgesic effect by intra-nasal ketorolac is faster than its oral form, and similar its intramuscular and intravenous counterparts.

Detailed Description
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Urinary stone disease (USD) leads to pain, diminished quality of life, missed work and school, chronic kidney disease, and renal failure.1-5 The prevalence of kidney stone disease in adults has risen to almost 9% as of 2010 in the United States (US). The 5-year recurrence rate without treatment is 53%.6,7 Increasing utilization of a ureteroscopic approach to treat urolithiasis has led to an increased proportion of stone patients undergoing ureteral stent placement. In the US, approximately 90% of patients receive a ureteral stent following ureteroscopy. Some patients that undergo ureteral stent placement experience significant and debilitating symptoms of urinary urgency, frequency, suprapubic and flank pain, and incontinence. Treatment of these symptoms has historically relied heavily on opioid pain medications. However, recent emphasis on risk associated with opioid medications has reduced their use, and paved the way for alternative approaches. As such, non-steroidal anti-inflammatory drugs (NSAIDs) have become an integral part of multimodal techniques at mitigating post operative pain and associated ureter stent discomfort. Ketorolac, an NSAID, can be used in the management of acute pain related to ureteral obstruction, renal colic, and indwelling ureter stent. There are four available formulations of ketorolac: oral, intra-muscular (IM), intra-nasal (IN), and intravenous (IV). Non-oral formulations are known to have faster onset of action and an earlier peak analgesic effect.8 As opposed to injectable (IM or IV) ketorolac that needs to be administered by a clinical provider, IN ketorolac may conveniently be self-administered.9 Furthermore, the favorable pharmacokinetics of IN ketorolac allow for its significant efficacy in providing timely pain relief without the need of opioid medications. However, one of the significant barriers of intra-nasal ketorolac is the cost. An intra-nasal course can cause upwards of $1500 compared to $20 of oral ketorolac. Ketorolac prevents unplanned renal colic-related clinical encounters post stent removal.10 Study team recently published the study team's results from a randomized trial comparing intramuscular injection of ketorolac to placebo at the time ureteral stent removal reduced the incidence of unplanned clinic returns or emergency room visits. While this trial was aimed at the small number of patients that develop severe ureteral colic following stent removal, investigators feel ketorolac's strong anti-inflammatory properties can be leveraged to mitigate acute indwelling ureteral stent symptoms. While it is not feasible to treat every stent patient empirically with IN ketorolac, there may be an identifiable subset of patients that may benefit from this formulation. Its favorable pharmacokinetics allow for its significant efficacy in providing timely pain relief without the need of opioid medications. This makes IN ketorolac an intriguing option that may decrease unplanned clinical encounters related to indwelling ureter stent discomfort. Especially when the cost of a post-operative emergency room visits which can include laboratory testing, computed tomography, IV medication and possible admission can dwarf the cost of IN ketorolac. Furthermore, a recent qualitative analysis published by Harper et al in the in the STudy to Enhance uNderstanding of sTent-associated Symptoms (STENTS) study reveal a highly variable patient experience with stents.11 For some, the negative experience of the stent can be life altering. Therefore, there is a critical need to improve the pain and quality of life of those requiring ureteral stenting. Ideally, this can be done in a directed way to offer more relief to those patients most at risk for severe symptoms.

Official Title
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Intra-nasal Ketorolac Versus Oral Diclofenac for Acute Ureteral Stent-associated Pain Following Ureteroscopy for Stone Disease

Conditions
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Post Operative Pain, Urolithiasis, Ureter Calculi, Stent Complication

Intervention / Treatment
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* Drug: intra-nasal ketorolac
* Drug: oral diclofenac


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years old English-speaking Candidate for unilateral ureteroscopy for treatment of urolithiasis Surgical plan includes placement of a ureteral stent Exclusion Criteria: Pregnant/nursing, prisoners, cognitively impaired Solitary kidney Stone in transplant kidney Anatomic abnormalities (i.e., ureteral stricture, infundibular stenosis, uretero-pelvic junction obstruction, horseshoe kidney, duplicated system) History of ureteral reconstruction History of nephrocalcinosis, medullary sponge kidney, cystinuria Immobility or relative immobility Planned staged ureteroscopy History of ureteral stent complication or poor tolerance or a ureteral stent Urinary tract infection or sepsis Current anticoagulation use (81 mg Aspirin permissible) NSAID contraindication (acute renal failure or chronic kidney disease, bleeding disorders, allergic reaction to NSAIDs, ulcer disease, auto-immune disease)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase I will consist of a single-arm open label pilot study. Prior to the initiation of a large-scale randomized trial, we propose a single-arm open label pilot study to evaluate the feasibility, practicality, and qualitative outcomes of utilizing intra-nasal ketorolac in patients with indwelling ureteral stents. We seek to enroll 20 patients for the initial pilot. Phase II will consist of a randomized trial comparing intranasal ketorolac to Diclofenac, a commonly used oral NSAID. , Diclofenac potassium. Following ureteroscopy and stent placement, patients will receive standard of care medications to mitigate post operative pain and stent discomfort, and will be randomized to receive either as needed intra-nasal ketorolac or oral diclofenac. We seek to enroll and randomize 60 patients in a 1:1 fashion. Analysis will be intention to treat.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sprix<br>Phase I will consist of a single-arm open label pilot study. Prior to the initiation of a large-scale randomized trial, we propose a single-arm open label pilot study to evaluate the feasibility, practicality, and qualitative outcomes of utilizing intra-nasal ketorolac in patients with indwelling ureteral stents. We seek to enroll 20 patients for the initial pilot. Phase II will consist of a randomized trial comparing intranasal ketorolac to Diclofenac, a commonly used oral NSAID. , Diclofenac potassium. Following ureteroscopy and stent placement, patients will receive standard of care medications to mitigate post operative pain and stent discomfort, and will be randomized to receive either as needed intra-nasal ketorolac or oral diclofenac. We seek to enroll and randomize 60 patients in a 1:1 fashion. Analysis will be intention to treat. | Drug: intra-nasal ketorolac<br>* Experimental group receiving intra-nasal ketorolac for management of post-operative pain following ureteroscopy for kidney stone, and associated ureter stent discomfort.<br>* Other names: Sprix;|
| Active Comparator: Diclofenac<br>Phase II will consist of a randomized trial comparing intranasal ketorolac to Diclofenac, a commonly used oral NSAID. , Diclofenac potassium. Following ureteroscopy and stent placement, patients will receive standard of care medications to mitigate post operative pain and stent discomfort, and will be randomized to receive either as needed intra-nasal ketorolac or oral diclofenac. We seek to enroll and randomize 60 patients in a 1:1 fashion. Analysis will be intention to treat. | Drug: oral diclofenac<br>* Control group to receive oral diclofenac, which is a comparable medication to intra-nasal ketorolac.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in pain scores as measured by USSQ Pain Survey | Associated pain burden will be measured using standardized Ureteral Stent Symptom Questionnaire (USSQ) Pain Survey. Possible scores range from 0-10, where lower scores indicate better outcome. | Baseline (before surgery in the pre-operative setting -Day 0), the day of ureter stent removal (Post-operative day 5 through 10) | 
| Change in pain scores as measured by PROMIS questionnaire | Associated pain burden will be measured using standardized Patient-Reported Outcome Measurement Information System (PROMIS) Pain Intensity and Interference questionnaire. Possible scores range from 0-10, where lower scores indicate better outcome. | Baseline (before surgery in the pre-operative setting -Day 0), the day of ureter stent removal (Post-operative day 5 through 10) | 
| Change in pain scores as measured by Likert Scale Questionnaire | Associated pain burden will be measured using standardized Likert Scale Questionnaire. Possible scores range from 0-10, where lower scores indicate better outcome. For those patients in the SPIRIX arm, they will be asked to complete the Likert Scale Questionnaire approximately 30 minutes after taking each SPIRIX dose. | Baseline (before surgery in the pre-operative setting -Day 0), the day of ureter stent removal (Post-operative day 5 through 10) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of unplanned clinical encounters | number of clinical encounters (i.e. telephone calls, MyChart messages, emergency room visits, hospital readmissions) related to ureter stent discomfort will be counted. | Post-operative setting -the day of ureter stent removal (Post-operative day 5 through 10) |