Intravenous Ketorolac Vs. Morphine In Children With Acute Abdominal Pain

Study Overview
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Brief Summary
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Appendicitis is a common condition in children 6-17 years of age, and the top reason for emergency surgery in Canada. Children with appendicitis can have very bad pain in their belly. Children often need pain medications given to them through a needle in their arm called an intravenous (IV). The most common IV pain medication is a type of opioid called morphine. We know that opioids work well to improve pain, but there are risks and side effects when taking them. There are non-opioid medications that doctors can give to patients, like ketorolac. Ketorolac helps decrease inflammation and pain and has fewer side effects when a patient takes it for a short period of time. Our past and present overuse of opioids, driven by an unproven assumption that opioids work best for pain, resulted in an Opioid Crisis and doctors are now looking for alternatives. To do this, we need to prove that there are other options to treat children's pain that are just as good as opioids, with less side effects. The goal of our study is to discover if school aged children who arrive at the emergency department with belly pain, improve just as much with ketorolac as they do with morphine. To answer this question, we will need a very large number of patients in a study that includes several hospitals across Canada. With a flip of a coin, each participant will either get a single dose of morphine or a single dose of ketorolac. To make sure that our pain assessment is impartial, no one will know which medicine the child received except the pharmacist who prepared the medicine.

Detailed Description
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Background: Appendicitis, the most common surgical diagnosis in Canadian children aged 6-17 years, accounts for  8000 admissions annually. Despite an ongoing opioid crisis, prescription narcotics remain a mainstay analgesic for children with suspected appendicitis. Ketorolac, a non-steroidal anti-inflammatory drug (NSAID), which has a safer adverse event (AE) profile than opioids, is commonly used in emergency departments (EDs) for adults; however, use in children is considered off label due to a lack of randomized trials in this patient population. We propose a multi-centre clinical trial to address this knowledge gap,informed by our team's successful pilot trial. Specific Aim 1: To determine if administering intravenous (IV) ketorolac is non inferior to IV morphine in reducing mean pain scores in children with suspected appendicitis. Hypothesis: IV ketorolac will be non-inferior to IV morphine Specific Aim 2: To determine between group differences in rates of AEs. Hypothesis: IV ketorolac will be associated with less AEs than IV morphine. Design: A randomized quadruple blind (participant, clinician, outcome assessor, investigator) parallel group double-dummy trial in 4 Canadian pediatric EDs. Eligible patients will be 6-17 years with 5-days of moderate-severe pain (vNRS ≥5 ) being investigated for suspected appendicitis, with intravenous (IV) access, will be randomized to either: IV ketorolac 0.5 mg/kg up to 30 mg (intervention) + IV morphine placebo (normal saline), or IV morphine 0.1 mg/kg up to 5 mg (active control) + IV ketorolac placebo (normal saline). Primary outcome: Between-group mean difference in pain on the vNRS at 60 minutes following administration. Safety outcome: Proportion of children experiencing AEs related to study drug administration. Secondary Outcomes: Between-group differences: (1) pain relief as measured on vNRS at 30, 90 and 120 minutes and at 6-8 hours; (2) proportion who achieves a 2-point vNRS (minimal important difference) pain score reduction at 60 and 120 minutes; (3) proportion of patients who change their baseline pain category (vNRS: mild 0-3, moderate 4-6, severe ≥7) at each time point; (4) time to effective analgesia as measured by the time when vNRS of <3 is achieved (5) proportion of patients requiring additional analgesia; (6) total opioids administered (i.e., morphine equivalent mg/kg within 8 hours of treatment); (7) frequency of specific types of AEs (e.g., dizziness); (8) frequency of delayed appendicitis diagnosis; and (9) Ramsay Sedation Score at 30, 60, 90 and 120 minutes. Sample size:With a non-inferiority margin of 1.0 (50% of the minimal important difference), 600 participants would give a power of 0.9 (1- β) to establish non-inferiority of ketorolac vs. morphine (significance level α = 0.05).

Official Title
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Intravenous Ketorolac Vs. Morphine In Children Presenting With Acute Abdominal Pain And/or Suspected Appendicitis: A Multi-centre Non-Inferiority Randomized Controlled Trial

Conditions
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Acute Pain, Abdomen, Acute, Abdominal Pain, Appendicitis, Emergencies, Child, Only

Intervention / Treatment
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* Drug: Ketorolac Tromethamine
* Drug: Morphine Sulfate
* Drug: normal saline
* Drug: Normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 6 to 17 years Abdominal pain ≤5 days duration Acute abdominal pain that is being investigated (suspected) by the clinical team for appendicitis Patient with IV cannula in situ or ordered Currently experiencing moderate to severe abdominal pain at rest or with movement: self-reported pain score ≥5 using the verbal Numerical Rating Scale Exclusion Criteria: Previous enrollment in the trial NSAID use within 3 hours and/or opioid use within 1 to 2 hours (1 hour post-IV or intra-nasal fentanyl and 2 hours post IV morphine). Children who need immediate resuscitation, are hemodynamically unstable as deemed by the clinical team or have a Canadian Triage Assessment Score of 1 Significant caregiver and/or child cognitive impairment precluding the ability to complete study questions. Chronic pain requiring daily analgesic use: confounding as response to analgesics maybe altered. History of severe undiagnosed gastrointestinal bleeding requiring medical intervention, peptic or duodenal ulcer disease or inflammatory bowel disease, coagulation disorders, prior cerebrovascular bleeding, known arterio-vascular malformations. History of minor gastrointestinal bleeding from conditions such as resolved fissures, polyps or allergic colitis will not exclude patients from participating. History of chronic and active interstitial kidney disease History of chronic and active hepatocellular disease: ketorolac is metabolized by the liver. Known or suspected pregnancy at the time of enrollment or breastfeeding females Known hypersensitivity to NSAIDs or opioids. Absence of a parent/guardian for children who are <16 years of age if they are not a mature minor. Inability to obtain consent due to a language barrier and the absence of language translator in person or by a phone translation service available in the ED.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 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: Two parallel interventional groups.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketorolac Tromethamine<br>Ketorolac tromethamine, an NSAID belonging to a group of non-opioid analgesics that inhibit the synthesis of prostaglandins and thromboxanes with strong analgesic and anti-inflammatory properties. It is the only non-opioid parenteral non-sedating analgesic available in Canada for use to treat acute pain in the emergency department. | Drug: Ketorolac Tromethamine<br>* Intravenous ketorolac given at 0.5 mg/kg of body weight up to a maximum of 30 mg in a single dose.<br>Drug: normal saline<br>* Intravenous normal saline placebo (labelled as morphine) given at 0.1 mg/kg of body weight up to a maximum of 5 mg in a single dose.<br>* Other names: Morphine Sulfate Placebo;|
| Active Comparator: Morphine Sulfate<br>An intravenous opioid that is commonly used as part of usual care for treament of pain in patients with acute abdominal pain and suspected appendicitis. | Drug: Morphine Sulfate<br>* Intravenous morphine given at 0.1 mg/kg of body weight up to a maximum of 5 mg in a single dose.<br>Drug: Normal saline<br>* Intravenous normal saline placebo (labelled as ketorolac) given at 0.5 mg/kg of body weight up to a maximum of 30 mg in a single dose.<br>* Other names: Ketorolac Tromethamine Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain relief as measured on the verbal numerical rating scale | Between group mean differences in pain as measured on an 11-point verbal Numerical Rating Scale (0 is no pain and 10 is worst pain ever) | 60 minutes post drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain relief as measured on the verbal numerical rating scale | Between group mean differences in pain as measured on an 11-point verbal | 30 minutes post drug administration | 
| Pain relief as measured on the verbal numerical rating scale | Between group mean differences in pain as measured on an 11-point verbal | 90 minutes post drug administration | 
| Pain relief as measured on the verbal numerical rating scale | Between group mean differences in pain as measured on an 11-point verbal | 120 minutes post drug administration | 
| Pain relief as measured on the verbal numerical rating scale | Between group mean differences in pain as measured on an 11-point verbal | 6 hours post drug administration | 
| Pain relief as measured on the verbal numerical rating scale during the ultrasound diagnostic | score from 0-10 on verbal numerical rating scale | up to 6 hours post drug administration | 
| Proportion who achieve the minimal important difference for pain relief | Proportion of participants who achieves the 2-point verbal Numerical Rating Scale minimal important difference pain score reduction | 60 minutes post drug administration | 
| Proportion who achieve the minimal important difference for pain relief | Proportion of participants who achieves the 2-point verbal Numerical Rating Scale minimal important difference pain score reduction | 120 minutes post drug administration | 
| Change in baseline pain category | Proportion of participants who change the severity of their baseline pain category. Pain categories on the verbal numerical rating scale as follows: mild = 0 to 4, moderate = 5 to 7, severe >7) | 30 minutes post drug administration | 
| Change in baseline pain category | Proportion of participants who change the severity of their baseline pain category. Pain categories on the verbal numerical rating scale as follows: mild = 0 to 4, moderate = 5 to 7, severe >7) | 60 minutes post drug administration | 
| Change in baseline pain category | Proportion of participants who change the severity of their baseline pain category. Pain categories on the verbal numerical rating scale as follows: mild = 0 to 4, moderate = 5 to 7, severe >7) | 90 minutes post drug administration | 
| Change in baseline pain category | Proportion of participants who change the severity of their baseline pain category. Pain categories on the verbal numerical rating scale as follows: mild = 0 to 4, moderate = 5 to 7, severe >7) | 120 minutes post drug administration | 
| Change in baseline pain category | Proportion of participants who change the severity of their baseline pain category. Pain categories on the verbal numerical rating scale as follows: mild = 0 to 4, moderate = 5 to 7, severe >7) | 6 hours post drug administration | 
| Time to effective analgesia | Duration of time from time of drug administration to time at which a verbal Numerical Rating Scale ≤3 is achieved. | up to 6 hours post drug administration | 
| Additional analgesia requirment | Proportion of participants requiring any additional analgesia in each trial arm | up to 6 hours post drug administration | 
| Total opioids administered | total morphine-equivalent mg/kg administered for all trial participants | up to 8 hours post drug administration | 
| Ramsay sedation score | Assessment of sedation levels post drug administration; score is 1-6 (1 is alert, 6 is not responsive) | 30 minutes post drug administration | 
| Ramsay sedation score | Assessment of sedation levels post drug administration; score is 1-6 (1 is alert, 6 is not responsive) | 60 minutes post drug administration | 
| Ramsay sedation score | Assessment of sedation levels post drug administration; score is 1-6 (1 is alert, 6 is not responsive) | 90 minutes post drug administration | 
| Ramsay sedation score | Assessment of sedation levels post drug administration; score is 1-6 (1 is alert, 6 is not responsive) | 120 minutes post drug administration | 
| Adverse events per participant | Frequency of specific adverse event occurrence per participant enrolled | up to 6 hours post drug administration | 
| Frequency of each specific adverse event | Frequency of each specific adverse event occurrence | up to 6 hours post drug administration |