Intranasal Ketorolac for Migraines

Overseen By Carlee Lenehan, MD

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: Washington University School of Medicine

Must not be taking: Antiplatelets, Anticoagulants, Antipsychotics, others

Disqualifiers: Renal impairment, Bleeding disorders, others

Stay on Your Current Meds You can continue your current medications while participating

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

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: Single session

120 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to determine if intranasal (IN) Ketorolac in combination with oral Prochlorperazine and Diphenhydramine is non-inferior to current migraine management which involves use of intravenous (IV) Ketorolac and oral adjuncts Prochlorperazine and diphenhydramine for reducing pain intensity in children with migraine headaches. The investigators hypothesize that IN ketorolac combined with these oral adjuncts is non-inferior to IV ketorolac and oral adjuncts in reducing acute migraine headache pain by a minimum clinically significant difference within 60 minutes of administration.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before participating. If you are taking NSAIDs (like ibuprofen) within six hours, or oral prochlorperazine, metoclopramide, or diphenhydramine within 12 hours, you cannot participate. Additionally, if you are on specific medications like antiplatelets, anticoagulants, or certain antidepressants, you will be excluded from the study.

What data supports the effectiveness of the drug for treating migraines?

Research shows that intranasal ketorolac, a drug used for pain relief, is effective in reducing migraine pain. In a study, 64% of patients experienced significant pain reduction after using ketorolac, and it helped decrease the need for emergency room visits. ^{1 2 3 4 5}

Is intranasal ketorolac safe for humans?

Intranasal ketorolac has been shown to have a safety profile similar to other forms of administration, with no adverse effects on the nasal passages or respiratory system in animal studies. It has also been used safely in humans for pain management, including in patients with migraines and postoperative pain. ^{1 2 4 6 7}

How is the drug ketorolac unique for treating migraines?

Intranasal ketorolac (SPRIX) is unique for treating migraines because it combines ketorolac, a non-opioid pain reliever, with lidocaine, a numbing agent, and is administered through the nose, offering a non-injection, non-oral option that can be quickly absorbed and effective for acute migraine relief. ^{1 2 4 8 9}

Research Team

Carlee Lenehan, MD

Principal Investigator

Washington University in St. Louis: st. louis childrens hospital

Eligibility Criteria

This trial is for children with migraines that are moderate to severe, affect daily activities, have specific characteristics like pulsating pain or nausea, and last between 1 to 72 hours. Participants must rate their pain at least 4/10 on the Faces Pain Scale.

Inclusion Criteria

My headache matches at least three of the listed features.

My pain level is at least 4 out of 10.

My headaches last between 1 and 72 hours.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive either intranasal ketorolac with oral adjuncts or intravenous ketorolac with oral adjuncts to manage migraine pain

Single session

1 visit (in-person)

Follow-up

Participants are monitored for changes in pain intensity using the Faces Pain Scale - Revised at multiple time points after treatment

2 hours

1 visit (in-person)

Treatment Details

Interventions

• Diphenhydramine
• Ketorolac
• Prochlorperazine

Trial Overview The study tests if nasal spray Ketorolac combined with oral Prochlorperazine and Diphenhydramine is as effective as IV Ketorolac for reducing migraine pain in kids within an hour of taking it.

Participant Groups

Group I: Intranasal Patients Experimental Treatment 3 Interventions

Intranasal ketorolac (1 spray (15.75mg) if 15kg-29.9kg and 2 sprays (31.5mg) if 30kg or heavier and oral adjuncts oral Prochlorperazine (Between 15-25 kg: dose of 2.5 mg; 26-50 kg: dose of 5 mg; \> 50 kg: dose of 10 mg, single maximum dose 10 mg) and oral Diphenhydramine (Between 15-25 kg: dose of 12.5 mg; 26-50 kg: dose of 25 mg; \> 50 kg: dose of 50 mg, single maximum dose 50mg)

Group II: Intravenous Patients Active Control 3 Interventions

IV ketorolac (0.5 mg/kg, maximum single dose of 30 mg) with oral adjuncts oral Prochlorperazine (Between 15-25 kg: dose of 2.5 mg; 26-50 kg: dose of 5 mg; \> 50 kg: dose of 10 mg, single maximum dose 10 mg) and oral Diphenhydramine (Between 15-25 kg: dose of 12.5 mg; 26-50 kg: dose of 25 mg; \> 50 kg: dose of 50 mg, single maximum dose 50mg)

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?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Assertio Holdings, Inc

Collaborator

Trials

1

Recruited

120+

Findings from Research

The intranasal formulation of ketorolac tromethamine, known as SPRIX, provides a similar pharmacokinetic profile to intramuscular administration, making it an effective option for treating moderately severe acute pain.

Toxicology studies in rats and rabbits indicate that SPRIX has a safety profile comparable to other administration routes, with no adverse effects observed on the nasal passages or respiratory system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel formulation of ketorolac tromethamine for intranasal administration: preclinical safety evaluation. Boyer, KC., McDonald, P., Zoetis, T.[2013]

In a trial involving 140 patients with moderate-to-severe migraines, the intranasal formulation of ketorolac tromethamine (ROX-828) showed significant improvements in pain relief compared to placebo at multiple time points, although it did not meet the primary endpoint at two hours.

ROX-828 was well tolerated, with nasal discomfort being the most common side effect, and it also significantly improved associated migraine symptoms like nausea and sensitivity to light and sound.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intranasal ketorolac tromethamine (SPRIX(R)) containing 6% of lidocaine (ROX-828) for acute treatment of migraine: safety and efficacy data from a phase II clinical trial. Pfaffenrath, V., Fenzl, E., Bregman, D., et al.[2013]

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]

In a study involving 16 patients with episodic migraines, self-injections of ketorolac tromethamine (Toradol) demonstrated a significant efficacy, with 64% of injections resulting in a good response and substantial pain reduction.

The self-injection method not only provided effective pain relief but also reduced the need for emergency room visits, with only 13% of usages failing to prevent the need for acute care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Self-administration of parenteral ketorolac tromethamine for head pain. Turkewitz, LJ., Casaly, JS., Dawson, GA., et al.[2019]

In a study involving 31 patients with severe migraines, ketorolac tromethamine was found to be significantly less effective than meperidine hydrochloride in reducing headache pain and improving clinical disability after one hour.

Only 44% of patients treated with meperidine experienced sustained headache relief at follow-up, compared to just 13% for those treated with ketorolac, indicating that meperidine may be a better option for emergency treatment of severe migraines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, double-blind, comparative study of the efficacy of ketorolac tromethamine versus meperidine in the treatment of severe migraine. Larkin, GL., Prescott, JE.[2019]

In a study of 4086 patients undergoing elective neurosurgery, those who received ketorolac had a significantly lower incidence of symptomatic intracranial hemorrhage (ICH) at 0.5% compared to 1.3% in those who did not receive the drug, suggesting a potential protective effect against bleeding.

Despite the lower observed risk of ICH in patients taking ketorolac, the adjusted odds ratio was close to 1, indicating that the findings may not be conclusive enough to definitively establish the safety of ketorolac in this surgical context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracranial hemorrhage requiring surgery in neurosurgical patients given ketorolac: a case-control study within a cohort (2001-2010). Magni, G., La Rosa, I., Melillo, G., et al.[2022]

In a study of 127 patients undergoing major surgery, intranasal ketorolac at a dose of 31.5 mg significantly reduced the need for supplemental morphine compared to placebo and the lower 10 mg dose, indicating its efficacy in managing postoperative pain.

The 31.5 mg dose of ketorolac also resulted in lower rates of pyrexia and tachycardia compared to placebo, suggesting a better safety profile while effectively controlling pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety and analgesic efficacy of intranasal ketorolac in patients with postoperative pain. Moodie, JE., Brown, CR., Bisley, EJ., et al.[2013]

The study found that after nasal inhalation of a radiolabelled ketorolac formulation, less than 0.5% of the dose reached the lungs, indicating minimal pulmonary deposition, regardless of the inhalation technique or posture used.

Most of the administered dose was deposited in the nasal cavity, with the best distribution observed when subjects were upright, and the drug cleared rapidly from the nasal cavity, with only 16-30% remaining after 10 minutes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pulmonary and nasal deposition of ketorolac tromethamine solution (SPRIX) following intranasal administration. Bacon, R., Newman, S., Rankin, L., et al.[2018]

A study involving 20 adolescents aged 12 to 17 showed that intranasal ketorolac is well tolerated with minimal side effects, making it a safe option for postoperative pain management.

The pharmacokinetics of intranasal ketorolac demonstrated a rapid increase in plasma concentration, with peak levels reached in about 52 minutes, suggesting it could be an effective alternative to intravenous administration for pain relief.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pharmacokinetics of ketorolac after single postoperative intranasal administration in adolescent patients. Drover, DR., Hammer, GB., Anderson, BJ.[2013]

References

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

A novel formulation of ketorolac tromethamine for intranasal administration: preclinical safety evaluation. [2013]

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

Intranasal ketorolac tromethamine (SPRIX(R)) containing 6% of lidocaine (ROX-828) for acute treatment of migraine: safety and efficacy data from a phase II clinical trial. [2013]

3. 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]

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

Self-administration of parenteral ketorolac tromethamine for head pain. [2019]

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

A randomized, double-blind, comparative study of the efficacy of ketorolac tromethamine versus meperidine in the treatment of severe migraine. [2019]

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

Intracranial hemorrhage requiring surgery in neurosurgical patients given ketorolac: a case-control study within a cohort (2001-2010). [2022]

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

The safety and analgesic efficacy of intranasal ketorolac in patients with postoperative pain. [2013]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Pulmonary and nasal deposition of ketorolac tromethamine solution (SPRIX) following intranasal administration. [2018]

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

The pharmacokinetics of ketorolac after single postoperative intranasal administration in adolescent patients. [2013]