Ketorolac Dosing for Acute Pain in Children

(KETODOSE Trial)

Recruiting at 1 trial location

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Hamilton Health Sciences Corporation

Must not be taking: Opioids, Daily analgesics

Disqualifiers: Cognitive impairment, Gastrointestinal bleed, 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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 8 hours

171 Participants Needed

Trial Summary

What is the purpose of this trial?

Hospital Scene #1: A 6-year-old arrives in the Emergency Department at McMaster Children's Hospital (MCH) complaining of pain in his lower right side. His Dad explains the pain has been going on for a few hours and that Advil and Tyelnol haven't helped at all. He's anxious and concerned about his son because he never complains about pain - so this must be bad. After he has been seen by the doctor, the appendix appears to be the problem and the boy needs to have it removed. Dad wants his son's pain to go away but is worried because he once got a high dose of a medication and had some unwanted side effects. Hospital Scene #2: A 14-year-old girl has been experiencing migraine headaches for the past months and is awaiting an appointment with a specialist. Today, however, the pain is the worst it's been. Mom has picked her up from school and brought her to MCH not knowing what else to do to help her. The Advil and Tylenol have not improved her pain. She desperately wants the pain to go away but is worried because she read that some pain medicines are used without any studies done to see if they work and if they are safe. (https://www.ottawalife.com/article/most-medications-prescribed-to-children-have-not-been-adequately-studied?c=9). In both cases, these children need medicine to help their pain. The treating doctors want to give them pain medicine that will 1) be safe and 2) make the pain go away. This is what parents and the child/teenager, and the doctors want too. Some pain medicines like opioids are often used to help with pain in children. Unfortunately, opioids can have bad side effects and can, when used incorrectly or for a long time, be addictive and even dangerous. A better option would be a non-opioid, like Ketorolac, which also helps pain but is safer and has fewer side effects. The information doctors have about how much Ketorolac to give a child, though, is what has been learned from research in adults. Like with any medication, the smallest amount that a child can take while still getting pain relief is best and safest. Why give more medicine and have a higher risk of getting a side effect, if a lower dose will do the trick? This is what the researchers don't know about Ketorolac and what this study aims to find out. Children 6-17 years old who are reporting bad pain when they are in the Emergency Department or admitted in hospital and who will be getting an intravenous line in their arm will be included in the study. Those who want to participate will understand that the goal of the study is to find out if a smaller amount of medicine improves pain as much as a larger amount. By random chance, like flipping a coin, the child will be placed into a treatment group. The difference between these treatment groups is the amount of Ketorolac they will get. One treatment will be the normal dose that doctors use at MCH, and the other two doses will be smaller. Neither the patient, parent nor doctor will know how much Ketorolac they are getting. Over two hours, the research nurse or assistant will ask the child how much pain they are in. Our research team will also measure how much time it took for the pain to get better, and whether the child had to take any other medicine to help with pain. The research team will also ask families and patients some questions to understand their perceptions of pain control, pain medicines and side effects they know of. This research is important because it may change the way that doctors treat children with pain, not just at MCH but around the world. The results of this study will be shared with doctors through conferences and scientific papers. It's also important that clinicians share information with parents and children so that they can understand more about pain medicines and how these medicines can be used safely with the lowest chance of side effects.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, if you use daily pain relievers, you cannot participate in the trial.

What data supports the idea that Ketorolac Dosing for Acute Pain in Children is an effective drug?

The available research does not provide any data on Ketorolac Dosing for Acute Pain in Children. All the studies focus on treatments for HIV in children, such as antiretroviral drugs, and do not mention Ketorolac or its effectiveness for pain management in children. ^{1 2 3 4 5}

What safety data exists for ketorolac in treating acute pain in children?

Existing safety data for ketorolac includes studies on its use in various forms and conditions. One study reports corneal ulceration and perforation with high doses of ketorolac tromethamine (Acular) after PRK. Another study compares the analgesic and emetic effects of intravenous ketorolac with morphine in children undergoing dental surgery, indicating limited published data on its use in pediatric analgesia. Additionally, ketorolac has been studied for its safety and efficacy in treating ocular inflammation and postoperative pain, with generally low reported side effects, though more research is needed to fully understand its safety profile. ^{6 7 8 9 10}

Is the drug Ketorolac Tromethamine a promising treatment for acute pain in children?

Yes, Ketorolac Tromethamine is a promising drug for treating acute pain in children. It has been shown to effectively manage moderate to severe pain, often reducing the need for stronger painkillers like morphine. It works quickly and has fewer side effects compared to some other pain medications. ^{7 10 11 12 13}

Eligibility Criteria

This trial is for children aged 6 to less than 18 experiencing moderate to severe acute pain, who are in the emergency department or hospitalized with an IV line already in place. It's not for kids with chronic kidney or liver diseases, those who've taken ketorolac or opioids recently, have a history of bleeding disorders, known pregnancy, NSAID or opioid allergies, cognitive impairments that prevent consent, or are post-operative.

Inclusion Criteria

Patient with IV cannula in situ or ordered

I have been experiencing acute pain for less than 30 days.

I am between 6 and 18 years old and have moderate to severe pain.

Exclusion Criteria

I have recently used ketorolac or opioids.

Inability to obtain consent

Either I or my child has cognitive impairment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive one of three doses of IV Ketorolac, with pain and adverse events monitored over 8 hours

8 hours

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

7 days

1 follow-up survey (virtual)

Treatment Details

Interventions

• Ketorolac Tromethamine

Trial Overview The study tests three different doses of Ketorolac Tromethamine—a non-opioid painkiller—to find the smallest effective dose for children's pain relief without unnecessary side effects. Participants will be randomly assigned to receive one of two smaller doses or the normal dose used at MCH and will be monitored over two hours for pain levels and additional medication needs.

Participant Groups

Group I: Low dose group B2 Experimental Treatment 1 Intervention

IV ketorolac 0.25 mg/kg to a maximum of 30 mg plus IV normal saline placebo given at 0.5 mg/kg to a maximum of 30 mg plus IV normal saline placebo 0.5 mg/kg to a maximum of 10 mg

Group II: Low dose group B1 Experimental Treatment 1 Intervention

IV ketorolac 0.5 mg/kg to a maximum of 10 mg plus IV normal saline placebo given at 0.25 mg/kg to a maximum of 30 mg plus IV normal saline placebo given at 0.5 mg/kg to a maximum of 30 mg

Group III: Standard dose group A Active Control 1 Intervention

IV ketorolac 0.5 mg/kg/dose up to a maximum dose of 30 mg plus IV normal saline placebo given at 0.25 mg/kg to a maximum of 30 mg plus IV normal saline placebo given at 0.5 mg/kg to a maximum of 10 mg

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

Approved in United States as Toradol for:

• Moderate to severe pain
• Rheumatoid arthritis
• Osteoarthritis
• Ankylosing spondylitis
• Menstrual disorders
• Headaches

Approved in European Union as Ketorolac for:

• Moderate to severe pain
• Rheumatoid arthritis
• Osteoarthritis
• Ankylosing spondylitis
• Menstrual disorders
• Headaches

Approved in Canada as Ketorolac for:

• Moderate to severe pain
• Rheumatoid arthritis
• Osteoarthritis
• Ankylosing spondylitis
• Menstrual disorders
• Headaches

Who Is Running the Clinical Trial?

Hamilton Health Sciences Corporation

Lead Sponsor

Trials

380

Recruited

345,000+

McMaster University

Collaborator

Trials

936

Recruited

2,630,000+

Findings from Research

In a study involving 24 children with advanced HIV infection, didanosine showed similar bioavailability when administered at a once-daily dose of 180 mg/m² compared to a twice-daily dose of 90 mg/m².

The relative bioavailability of didanosine was found to be 0.95 ± 0.49, suggesting that once-daily dosing could be clinically effective for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioavailability of once- and twice-daily regimens of didanosine in human immunodeficiency virus-infected children. Abreu, T., Plaisance, K., Rexroad, V., et al.[2021]

In a study involving 55 adolescents with HIV-1, doravirine and the fixed-dose combination (DOR FDC) of doravirine/lamivudine/tenofovir disoproxil fumarate demonstrated effective pharmacokinetics similar to those seen in adults, indicating its potential for use in this age group.

The treatment was well-tolerated, with no serious drug-related adverse events, and 93.3% of participants maintained undetectable HIV-1 RNA levels (<40 copies/mL) after 24 weeks, showcasing its efficacy in managing HIV-1 in adolescents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, Tolerability, and Safety of Doravirine and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate Fixed-Dose Combination Tablets in Adolescents Living With HIV: Week 24 Results From IMPAACT 2014. Melvin, AJ., Yee, KL., Gray, KP., et al.[2023]

In a study of 318 HIV-infected children and adolescents, 69% received off-label antiretroviral (ARV) medications, primarily due to treatment failure, highlighting the commonality of off-label use in pediatric HIV treatment.

Incorrect dosing was prevalent, with 10% of patients either overdosed or underdosed; notably, underdosing was linked to a significantly higher rate of treatment failure (50% vs. 26% for overdosed patients), emphasizing the need for careful dosing and suitable formulations for younger patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Description and consequences of prescribing off-label antiretrovirals in the Madrid Cohort of HIV-infected children over a quarter of a century (1988-2012). Fernández-Cooke, E., Rojas, P., Holguin, A., et al.[2016]

A standardized drug dosage table for antiretroviral treatment (ART) was found to be highly acceptable among doctors, with 94% of surveyed physicians reporting it made prescribing easier and reduced calculation errors.

In a study of 49 children prescribed ARVs, less than 5% experienced adverse side effects, and all ARV-naïve children achieved undetectable viral loads within six months, demonstrating the safety and efficacy of the standardized dosing approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A drug dosage table is a useful tool to facilitate prescriptions of antiretroviral drugs for children in Thailand. Ponnet, M., Frederix, K., Petdachai, W., et al.[2019]

Lamivudine, an antiretroviral medication, was well-tolerated in a study of 90 HIV-infected children, showing significant decreases in HIV RNA levels and stable CD4 and CD8 cell counts over 24 weeks.

While lamivudine demonstrated virologic activity, some patients developed resistance to the drug by 12 weeks, suggesting that it may be more effective when used in combination with other antiretroviral therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lamivudine in children with human immunodeficiency virus infection: a phase I/II study. The National Cancer Institute Pediatric Branch-Human Immunodeficiency Virus Working Group. Lewis, LL., Venzon, D., Church, J., et al.[2019]

A case study of a 31-year-old man revealed that excessive use of ketorolac tromethamine (Acula) after PRK led to corneal ulceration and perforation, necessitating surgical intervention.

The findings highlight the importance of proper patient education regarding the use of topical NSAIDs post-surgery to prevent complications like corneal damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Corneal ulceration and perforation with ketorolac tromethamine (Acular) use after PRK. Mian, SI., Gupta, A., Pineda, R.[2019]

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]

In a study involving 200 patients undergoing photorefractive keratectomy, topical ketorolac tromethamine 0.5% was found to provide significantly greater pain relief compared to its vehicle, with patients experiencing less pain intensity and a longer time before needing additional pain medication.

The ketorolac group also reported fewer side effects, such as sleep difficulties and ocular discomfort, and overall, the treatment was deemed safe with minimal adverse events, indicating its efficacy and safety for post-surgery pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analgesic efficacy and safety of ketorolac after photorefractive keratectomy. Ketorolac Study Group. Rajpal, RK., Cooperman, BB.[2022]

In a multicenter study involving patients with moderate to severe inflammation after cataract surgery, ketorolac tromethamine 0.5% was significantly more effective than a placebo in reducing inflammation and associated symptoms like pain and photophobia.

The treatment was found to be safe, with no significant differences in visual acuity or adverse events compared to the placebo, indicating that ketorolac is a reliable option for managing post-surgical inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketorolac tromethamine 0.5% ophthalmic solution in the treatment of moderate to severe ocular inflammation after cataract surgery: a randomized, vehicle-controlled clinical trial. Heier, J., Cheetham, JK., Degryse, R., et al.[2019]

Ketorolac tromethamine is an effective nonsteroidal anti-inflammatory drug (NSAID) for managing moderate to severe postoperative pain, reducing the need for opioid analgesics, which can help minimize opioid-related side effects.

Administered intramuscularly, ketorolac reaches peak plasma levels in about 45 to 50 minutes and has a low incidence of side effects, making it a promising option for both inpatient and outpatient pain management, although further research is needed to fully understand its role.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketorolac: a new parenteral nonsteroidal anti-inflammatory drug for postoperative pain management. Lassen, K., Epstein-Stiles, M., Olsson, GL.[2013]

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]

Ketorolac tromethamine is effective for treating moderate to very severe postoperative pain, with oral doses of 10 mg and higher showing significant superiority over placebo and comparable efficacy to morphine.

The drug is well tolerated, with fewer adverse events compared to opioid pain relievers, making it a safer alternative for postoperative pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analgesic efficacy and safety of single-dose oral and intramuscular ketorolac tromethamine for postoperative pain. Brown, CR., Moodie, JE., Dickie, G., et al.[2013]

In a study involving 40 patients with severe odontogenic pain, ketorolac tromethamine (KT) significantly reduced pain levels compared to a placebo, with patients reporting negligible discomfort by 90 minutes post-injection.

KT effectively alleviates severe pain within 40 minutes of administration, demonstrating its efficacy as an analgesic with minimal side effects, such as lightheadedness and injection site pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Utilization of ketorolac tromethamine for control of severe odontogenic pain. Curtis, P., Gartman, LA., Green, DB.[2013]

References

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

Bioavailability of once- and twice-daily regimens of didanosine in human immunodeficiency virus-infected children. [2021]

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

Pharmacokinetics, Tolerability, and Safety of Doravirine and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate Fixed-Dose Combination Tablets in Adolescents Living With HIV: Week 24 Results From IMPAACT 2014. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Description and consequences of prescribing off-label antiretrovirals in the Madrid Cohort of HIV-infected children over a quarter of a century (1988-2012). [2016]

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

A drug dosage table is a useful tool to facilitate prescriptions of antiretroviral drugs for children in Thailand. [2019]

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

Lamivudine in children with human immunodeficiency virus infection: a phase I/II study. The National Cancer Institute Pediatric Branch-Human Immunodeficiency Virus Working Group. [2019]

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

Corneal ulceration and perforation with ketorolac tromethamine (Acular) use after PRK. [2019]

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

Analgesic efficacy and safety of ketorolac after photorefractive keratectomy. Ketorolac Study Group. [2022]

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

Ketorolac tromethamine 0.5% ophthalmic solution in the treatment of moderate to severe ocular inflammation after cataract surgery: a randomized, vehicle-controlled clinical trial. [2019]

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

Ketorolac: a new parenteral nonsteroidal anti-inflammatory drug for postoperative pain management. [2013]

11. 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]

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

Analgesic efficacy and safety of single-dose oral and intramuscular ketorolac tromethamine for postoperative pain. [2013]

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

Utilization of ketorolac tromethamine for control of severe odontogenic pain. [2013]