Non-Steroidal or Opioid Analgesia Use for Children With Musculoskeletal Injuries
Condition: Musculoskeletal Injury
MeSH terms: Wounds and Injuries
Study type: Interventional
Phase: Phase 2

Summary: 
      Musculoskeletal (MSK) injuries, including limb injuries, are the most common cause for
      Emergency Department (ED) visits for children with pain. Broken arms and legs are known to
      cause moderate to severe pain in most children, yet previous research shows that children's
      pain in the emergency department is still under-treated. Further, children are less likely to
      receive appropriate pain medicine than adults with similar injuries.

      The purpose of this research study is to compare the effectiveness and safety of 3 different
      possible medication combinations, for the pain management of children with acute MSK limb
      injuries. The pain medicines the investigators are studying are ibuprofen (Advil/Motrin),
      acetaminophen (Tylenol/Tempra), and hydromorphone (Dilaudid).

      This study will consist of 2 trials that will be run simultaneously. Eligible caregiver/
      child pairs presenting to the emergency department with acute MSK limb injury will decide in
      which trial they wish to participate: the Opioid trial or the Non-Opioid trial. If they
      select the Non-opioid trial, they will have an equal chance of receiving either (a) Ibuprofen
      OR (b) Ibuprofen and acetaminophen. If they select the Opioid trial, they will have an equal
      chance of receiving either (a) Ibuprofen OR (b) Ibuprofen and acetaminophen OR (c) Ibuprofen
      and hydromorphone. Regardless of which study they choose, their child will, at minimum,
      receive Ibuprofen (Advil/Motrin) for their pain. All study medicines will be given in oral
      liquid form.

      This study will help the investigators figure out which pain medicine or combination of pain
      medicines works best for children with limb injuries. Promotion of adequate acute pain
      treatment of children presenting to the ED may help prevent the known short and long-term
      effects of inadequately treated pain in children, including unpleasant memories, stress and
      anxiety upon future visits to healthcare, and compromised functional outcomes such as missed
      school.
    

Detailed description: 
      Rationale:

      Multiple national and international organizations, including the American Academy of
      Pediatrics (AAP), have voiced concern over the emergency departments' (EDs) ability and
      willingness to provide appropriate analgesia for children's pain. Musculoskeletal (MSK)
      injury is a very common cause for ED visits for children with pain, with a child's risk of
      sustaining a fracture ranging from 27-42% by the age of 16 years. MSK injury is known to
      generate moderate to severe pain in most children and the ED serves as the critical entry
      point for these injured children. Despite three decades of pain research in this area, recent
      evidence confirms that ED pain management in children is still suboptimal. A retrospective
      cohort study of children presenting to the ED with an isolated long-bone fracture showed
      almost 1/3 received inadequate medication and 59% received no pain medications during the
      critical first hour of assessment. Previous studies have demonstrated that only 35% of
      children presenting to a Canadian pediatric ED with fractures or severe sprains received any
      analgesic. Further, a medical record review of two Canadian EDs showed unacceptably long
      delays in provision of initial analgesia, with children waiting a mean of 118 minutes to the
      provision of first analgesia.

      The AAP's consensus statement on the assessment and management of pain in children recommends
      acetaminophen, ibuprofen, and opioids as the top three medication choices for the treatment
      of acute pain in children. These are also the top three most commonly used treatments in the
      ED for children with MSK injury pain. It stands to reason that clinicians (and certainly
      patients and their families) would prefer medication that has the best efficacy and safety
      profile. Although not based on robust evidence, there has recently been a concerted movement
      to limit opioid use in children. This is due, in part, to recent controversial publications
      and the Centre for Disease Control (CDC)'s position statement regarding opioid use in adults.
      Clinicians are increasingly less likely to prescribe oral opioids to younger children, and
      caregivers are increasingly less willing to accept or administer them.

      Clinicians are currently seeking effective (and for many, non-opioid) oral analgesic options
      for their pediatric patients. Researchers have yet to identify the optimal acute pain
      management strategy for children with a suspected fracture, as very few studies of analgesic
      combination therapy for this injury exist, and monotherapy has been shown to be inadequate
      50% of the time. This team's previous work has demonstrated that a combination of oral
      morphine with ibuprofen was no more effective and was less safe than oral ibuprofen, alone,
      for suspected fracture pain. Similarly, oxycodone was no more effective and was less safe
      than ibuprofen for post-discharge fracture pain. There is some emerging work from non-ED
      settings to suggest that oral hydromorphone may be an effective alternative to these two
      opioid medications. The investigators wish to study if acetaminophen or hydromorphone, when
      added to ibuprofen, offers more clinical pain relief than ibuprofen alone. They also wish to
      study if the combination of hydromorphone and ibuprofen is more clinically effective than the
      combination of acetaminophen with ibuprofen. This study, which will consist of two clinical
      trials, will inform health-care decisions by providing evidence for the effectiveness and
      safety of commonly prescribed analgesic combination therapies, and compare them to the most
      commonly used monotherapy, ibuprofen.

      Methods:

      This study will be comprised of two Phase 2, six-centre, randomized, double blind,
      placebo-controlled trials that will be run simultaneously. These two 'sister trials will be
      run simultaneously within this novel preference-informed complementary trial design.
      Caregiver/child pairs presenting to the ED with acute MSK limb injury will decide in which
      trial they wish to participate: the Opioid trial or the Non-Opioid trial.

      Those willing to consider an Opioid will be randomized to receive either single-dose: (a)
      oral ibuprofen (10mg/kg, max 600mg) plus 2 placebos (both oral hydromorphone and
      acetaminophen), OR (b) oral ibuprofen (10mg/kg, max 600mg) + oral acetaminophen (15 mg/kg,
      max 1000mg) plus hydromorphone placebo OR (c) oral ibuprofen (10mg/kg) + oral hydromorphone
      (0.05 mg/kg, max 5 mg) plus acetaminophen placebo. Those not willing to consider an opioid
      will be enrolled in the Non-Opioid trial and will be randomized to receive a single dose of
      (a) oral ibuprofen (10mg/kg, max 600mg) + oral acetaminophen (15 mg/kg, max 1000mg) OR (b)
      oral ibuprofen (10mg/kg, max 600mg) + oral acetaminophen placebo. Those without a preference
      for either trial will be assigned to the Opioid trial, as this one includes all three options
      of possible medication combinations. The investigators will measure pain scores, assess
      safety, and acquire other study measures, at designated study time points.
    

Intervention name(s): Ibuprofen; Acetaminophen; Hydromorphone; Acetaminophen placebo; Hydromorphone placebo
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): 10mg/kg, maximum 600mg; Oral liquid; 15mg/kg, maximum 1000mg; Oral liquid; 0.05mg/kg, maximum 5 mg; Oral liquid; Oral liquid; Oral liquid
Other intervention name(s): Advil; Motrin; Tylenol; Tempra; Dilaudid; pms-Hydromorphone
Intervention MeSH terms: Acetaminophen; Ibuprofen; Hydromorphone
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This study will be comprised of two Phase 2, six-centre, randomized, double blind, placebo-controlled trials that will be run simultaneously. The investigators expect that the number of participants recruited and the time to completion of both trials will be more efficient as recruitment for both will occur simultaneously. They propose to conduct this study with a novel preference-informed complementary trial design, in which they will conduct two simultaneous 'sister' trials. Caregiver/child pairs presenting to the ED with acute MSK limb injury will decide in which trial they wish to participate: the Opioid trial or the Non-Opioid trial. The design of each trial will be informed by its sister, or complementary, trial. Once the caregiver/child pair has chosen their preferred trial, conduct within each trial will follow traditional randomized, double-blind placebo-controlled superiority trial methodology. Study endpoints will be identical for both trials within this study.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Pediatrics; Emergency; Analgesia; Opioids; Combination therapy; Ibuprofen; Acetaminophen; Hydromorphone