Ketorolac vs. Morphine for Acute Abdominal Pain in Children

(KETOAPP Trial)

Overseen By Mohamed M Eltorki, MBChB, MSc

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: University of Calgary

Must not be taking: NSAIDs, Opioids

Disqualifiers: Cognitive impairment, Chronic pain, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

Duration: 1 day

495 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that participants have not used NSAIDs within 3 hours and opioids within 1 to 2 hours before enrollment. If you are currently taking these medications, you may need to stop them for a short period before participating.

What data supports the effectiveness of the drug ketorolac compared to morphine for acute abdominal pain in children?

Research shows that ketorolac is effective for pain relief in various conditions, such as postoperative pain and cancer pain, with fewer side effects compared to morphine. In a study on postoperative pain, ketorolac was found to be as effective as higher doses of morphine, with fewer reports of drowsiness. ^{1 2 3 4 5}

Is ketorolac safe compared to morphine for treating pain in children?

Ketorolac has been shown to be a safe and effective pain reliever in various studies, with fewer side effects compared to morphine, which can cause drowsiness and nausea. In studies involving both adults and children, ketorolac was generally well-tolerated, with fewer patients stopping its use due to side effects compared to morphine. ^{1 2 5 6 7}

How does the drug ketorolac differ from morphine for treating acute abdominal pain in children?

Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) that provides pain relief without the risk of respiratory depression or drug abuse potential associated with morphine, an opioid. While ketorolac may take longer to provide pain relief, it has a longer duration of action compared to morphine. ^{2 5 7 8 9}

What is the purpose of this trial?

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.

Research Team

Mohamed Eltorki, MBChB

Principal Investigator

University of Calgary

Eligibility Criteria

This trial is for children aged 6-17 with severe belly pain, suspected of appendicitis, and who have or will get an IV. They must be in moderate to severe pain at rest or when moving, scoring ≥5 on a pain scale.

Inclusion Criteria

My abdominal pain has lasted 5 days or less.

I am being checked for appendicitis due to acute abdominal pain.

I have an IV line in place or one has been ordered for me.

Exclusion Criteria

I or my caregiver/child cannot complete study questions due to cognitive issues.

I have taken NSAIDs within 3 hours or opioids within 1-2 hours.

Known or suspected pregnancy at the time of enrollment or breastfeeding females

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive a single dose of either IV ketorolac or IV morphine, with pain assessments conducted at multiple time points post-administration

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including adverse events and additional analgesia requirements

8 hours

1 visit (in-person)

Treatment Details

Interventions

• Ketorolac
• Morphine

Trial Overview The study compares the effectiveness of Ketorolac (a non-opioid) versus Morphine (an opioid) for treating acute abdominal pain in children. Participants are randomly given one dose of either drug without knowing which one they received.

Participant Groups

Group I: Ketorolac Tromethamine Experimental Treatment 2 Interventions

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.

Group II: Morphine Sulfate Active Control 2 Interventions

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.

Ketorolac is already approved in United States, European Union, Switzerland for the following indications:

Approved in United States as Toradol for:

• Moderate to severe pain
• Postoperative pain
• Dysmenorrhea
• Idiopathic pericarditis
• Ocular itching

Approved in European Union as Toradol for:

• Moderate to severe pain
• Postoperative pain
• Dysmenorrhea

Approved in United States as Acular for:

• Ocular itching
• Inflammation after eye surgery

Approved in United States as Sprix for:

• Moderate to severe pain

Approved in Switzerland as Ketorolac for:

• Moderate to severe pain
• Postoperative pain

Who Is Running the Clinical Trial?

University of Calgary

Lead Sponsor

Trials

827

Recruited

902,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Findings from Research

In a study involving 155 patients, ketorolac tromethamine was found to provide better pain relief than morphine sulfate at lower doses (30 and 90 mg) for moderate to severe postoperative pain, especially after the first hour.

Ketorolac demonstrated a favorable safety profile, with no serious side effects reported, while morphine was associated with somnolence in 8% of patients, highlighting ketorolac as a safe and effective alternative for pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketorolac tromethamine as compared with morphine sulfate for treatment of postoperative pain. O'Hara, DA., Fragen, RJ., Kinzer, M., et al.[2022]

This pilot trial aims to assess the feasibility of comparing the effectiveness of ketorolac and morphine for treating acute abdominal pain in children suspected of having appendicitis, with a target enrollment of 100 participants and a consent rate of at least 40%.

The study is designed as a double-dummy randomized controlled trial, ensuring that both participants and clinicians are blinded to the treatment, which will help provide reliable data on the safety and efficacy of these analgesics in a pediatric emergency setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous ketorolac versus morphine in children presenting with suspected appendicitis: a pilot single-centre non-inferiority randomised controlled trial. Eltorki, M., Busse, JW., Freedman, SB., et al.[2022]

In a study of 27 pediatric patients undergoing orthopedic surgeries, ketorolac significantly reduced the need for morphine compared to a control group, indicating its effectiveness in managing postoperative pain.

Patients receiving ketorolac experienced fewer gastrointestinal side effects and had a shorter hospital stay, demonstrating that it is a safe alternative to morphine for pain management in pediatric orthopedic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of ketorolac in decreasing length of stay and narcotic complications in the postoperative pediatric orthopaedic patient. Eberson, CP., Pacicca, DM., Ehrlich, MG.[2013]

In a study involving 131 children aged 4-17 years with suspected fractures or dislocations, both sublingual ketorolac and tramadol significantly reduced pain, with mean pain scores dropping from eight to four for ketorolac and five for tramadol after 100 minutes.

There were no significant differences in pain relief or adverse effects between the two medications, indicating that both are equally effective for managing pain in pediatric patients with extremity injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sublingual ketorolac versus sublingual tramadol for moderate to severe post-traumatic bone pain in children: a double-blind, randomised, controlled trial. Neri, E., Maestro, A., Minen, F., et al.[2016]

In a study involving 51 patients with moderate to severe cancer pain, ketorolac tromethamine and morphine showed no significant difference in overall analgesic efficacy, indicating that ketorolac can be an effective alternative for pain management.

While 57% of patients on ketorolac and 74% on morphine changed their analgesic, significantly more patients discontinued ketorolac due to inadequate pain relief, whereas more patients stopped morphine due to side effects like nausea, suggesting ketorolac has a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative-study of intramuscular ketorolac tromethamine and morphine in patients experiencing cancer pain. Jameel, A., Stein, R., Rawson, N., et al.[2019]

In a study involving 176 postoperative patients, ketorolac (10 mg orally) provided analgesic efficacy comparable to both 5 mg and 10 mg doses of morphine, significantly outperforming placebo.

Ketorolac is a safe and effective option for managing acute postoperative pain, serving as a non-opioid alternative to traditional opioid therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of ketorolac in the management of postoperative pain. DeAndrade, JR., Maslanka, M., Maneatis, T., et al.[2022]

In a study involving 120 children aged 2-10 years undergoing dental surgery, intravenous ketorolac at doses of 0.75, 1.0, and 1.5 mg/kg was found to be as effective as morphine (0.1 mg/kg) for pain relief.

Ketorolac significantly reduced the incidence of postoperative vomiting compared to morphine, making it a safer alternative for pediatric analgesia in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effects of three doses of intravenous ketorolac or morphine on emesis and analgesia for restorative dental surgery in children. Purday, JP., Reichert, CC., Merrick, PM.[2018]

Ketorolac tromethamine is an effective injectable nonsteroidal anti-inflammatory drug for acute pain management, showing analgesic potency comparable to morphine without the risk of respiratory depression or abuse potential.

It has a longer duration of action than morphine and is safer for patients since it has less impact on the central nervous system, although it is not recommended for use in obstetric analgesia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketorolac: an injectable NSAID. DiPalma, JR.[2013]

In a study of 92 children aged 3 to 12, both intravenous morphine and ketorolac effectively provided pain relief for moderate to severe postsurgical pain, with morphine requiring fewer doses for analgesia.

While morphine provided quicker pain relief, ketorolac offered a longer duration of analgesia and was associated with fewer side effects, making it a viable alternative for managing pain in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of intravenous ketorolac with morphine for postoperative pain in children. Maunuksela, EL., Kokki, H., Bullingham, RE.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Ketorolac tromethamine as compared with morphine sulfate for treatment of postoperative pain. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Intravenous ketorolac versus morphine in children presenting with suspected appendicitis: a pilot single-centre non-inferiority randomised controlled trial. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

The role of ketorolac in decreasing length of stay and narcotic complications in the postoperative pediatric orthopaedic patient. [2013]

4. England pubmed.ncbi.nlm.nih.gov

Sublingual ketorolac versus sublingual tramadol for moderate to severe post-traumatic bone pain in children: a double-blind, randomised, controlled trial. [2016]

5. Greece pubmed.ncbi.nlm.nih.gov

Comparative-study of intramuscular ketorolac tromethamine and morphine in patients experiencing cancer pain. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

The use of ketorolac in the management of postoperative pain. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Comparative effects of three doses of intravenous ketorolac or morphine on emesis and analgesia for restorative dental surgery in children. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Ketorolac: an injectable NSAID. [2013]

9. United States pubmed.ncbi.nlm.nih.gov

Comparison of intravenous ketorolac with morphine for postoperative pain in children. [2019]