Ketorolac for Moderate to Severe Abdominal Pain in Children
Condition: Abdominal Pain; Appendicitis; Analgesia; Child, Only; Emergencies
MeSH terms: Appendicitis; Emergencies; Abdominal Pain
Study type: Interventional
Phase: Phase 3

Summary: 
      In children and adolescents (older than 6 years in age) who arrive in the pediatric emergency
      department because they have been having 5 days or less of abdominal pain (possible
      appendicitis), will patients who are treated with ketorolac get just as much pain relief as
      those patients treated with morphine?

      To answer this research question, we will need a large number of patients in a study. To
      ensure we have enough patients, we must include many hospitals in different cities and
      provinces in the same study. Before doing this, though, we must first test a smaller version
      of the study in our center at McMaster Children's hosptial. The goal of doing this at
      McMaster first is to make sure or understand:

        1. We can enroll enough people in our study over 1 year

        2. We can make sure that all the information we collect from patients is complete and
           nothing is missing

        3. Reasons behind why people don't want to participate in the study

        4. How satisfied patients and their caregivers were with the study
    

Detailed description: 
      Background/Rationale: Appendicitis is the most common emergent surgical diagnosis among
      children between 5-17 years in age and accounts for 8000 admissions annually. Diagnosing
      appendicitis is time consuming (4-6 hours) as it requires laboratory tests and
      ultrasonography. This occurs while patients experience significant abdominal pain secondary
      to infection and localized or generalized peritonitis. Opioids have been the most prescribed
      analgesic for patients with suspected appendicitis, despite an ongoing opioid crisis. Our
      research shows that 60% of physicians use morphine or other opioids, while 40% will use
      non-steroidal anti-inflammatory drug (NSAID) or other non-opioids. Even though ketorolac
      (NSAID) is commonly used in the Emergency Department (ED) for renal colic, abdominal pain and
      migraine headaches, and has a safer side effect profile than morphine, all such uses in
      children are "off label" as there are virtually no controlled trials for children to inform
      practice.

      Objective: To determine if it is feasible to conduct a large multi-centre randomized non
      inferiority trial comparing ketorolac to morphine for treating moderate to severe abdominal
      pain, in children 6 years in age or older, with clinically suspected appendicitis.

      Hypothesis: We hypothesize that it will be feasible to conduct a large trial based on a
      recruitment rate of ≥40% of eligible patients approached for consent.

      Study Design: Our trial is a single-centre, block randomized, non-inferiority, double-dummy,
      doubleblind, feasibility pilot trial. Patients ≥ 6 years in age, who have ≤ 5 days of
      moderate-severe pain as defined by our validated 11-point verbal numeric rating scale (VNRS)
      ≥ 5 and are being investigated for suspected appendicitis with intravenous (IV) access in
      situ or ordered, will be randomized to either: (1) IV ketorolac 0.5 mg/kg up to 30 mg
      (intervention) + IV morphine placebo, or (2) IV morphine 0.1 mg/kg up to 5 mg (active
      control) + IV ketorolac placebo. The total sample size is 100 participants. The study drugs
      will be identical in appearance, consistency and smell. The double-dummy design will ensure
      blinding is maintained for bedside clinical staff, research personnel and patients. Our study
      prioritized patient comfort and will largely mimic standard care. Pharmacologic
      co-interventions will be allowed but limited to acetaminophen (commonly used as first-line
      therapy). Participants in both groups will be allowed rescue therapy (morphine 0.5 mg/kg)
      within 60 minutes of our intervention. We will screen the ED daily for eligible patients as
      well as include all eligible patients for the New Investigator Fund (NIF)-funded quality
      improvement pathway we employed to streamline care for all ED appendicitis patients. We have
      a robust research program in the ED that includes students, a full-time research coordinator
      and several paid research assistants who screen eligible patients and approach them for
      consent and enrollment. Our entire project can be completed with NIF support within an
      18-month study period.

      Primary Outcome: Feasibility of our study design is the primary outcome of this pilot trial.
      Primary feasibility outcomes include: (1) proportion of patients consented from total
      eligible patients approached; (2) proportion of patients who completed clinical outcome
      assessment; and, (3) proportion of missing items on individual data collection forms. Our
      feasibility threshold is to recruit at least 40% of eligible patients who were approached to
      consent. Other thresholds include recruiting ≥8 participants/month on average and having at
      least 90% of participants complete all the outcome assessments at 30, 60, 90 and 120 minutes.

      Summary: Acute pain in children and youth is an area that is understudied and affects
      thousands of Canadian children. Despite short -and long-term adverse effects including
      dependence, and well designed comparative effectiveness trials, opioids continue to be
      overused in surgical patients. Ketorolac is a promising well-established NSAID that is
      available for IV, has a better short-term side effect profile and is not known as a substance
      of misuse. Our pilot will provide valuable feasibility data for a larger, future multicenter
      trial.
    

Intervention name(s): Ketorolac Tromethamine 10 MG/ML; Morphine Sulfate 10Mg/1mL Injection
Intervention type(s): Drug; Drug
Intervention description(s): Non-Steroidal-Anti-Inflammatory given intravenously.; Opioid commonly used for acute abdominal pain given intravenously.
Intervention MeSH terms: Ketorolac; Ketorolac Tromethamine; Morphine
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: double dummy design
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment