Intravenous Ketorolac Vs. Morphine In Children With Acute Abdominal Pain

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).

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.