Intravenous Ketorolac and Metoclopramide for Pediatric Migraine in the Emergency Department (EDMigraine-4)
Migraine headaches are a common problem for children. When treatment at home fails, children may benefit from intravenous treatment administered in a hospital setting like the Emergency Department. Most treatments used however have only been tested in adults and the best treatment strategy for children is not always clear. The combination of more than one medication is frequently prescribed in Canadian Emergency Departments. The purpose of this study is to investigate whether the combination of ketorolac (an anti-inflammatory pain medication) and metoclopramide (an anti-nauseant that may also relieve migraine headaches) is better than metoclopramide by itself.
Migraine With Aura
Migraine Without Aura
Drug: Ketorolac Tromethamine
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Efficacy of Combination Therapy With Intravenous Ketorolac and Metoclopramide for Pediatric Migraine Therapy in the Emergency Department|
- Mean reduction in pain intensity [ Time Frame: 2 hours ] [ Designated as safety issue: No ]Measured on Visual Analogue Scale (VAS).
- Pain freedom [ Time Frame: 2 hours ] [ Designated as safety issue: No ]VAS=0
- Headache relief - 33 [ Time Frame: 2 hours ] [ Designated as safety issue: No ]Defined as a 33% reduction on the VAS.
- Headache relief - 50 [ Time Frame: 2 hours ] [ Designated as safety issue: No ]Defined as a 50% reduction on the VAS
- Presence of nausea [ Time Frame: 2 hours ] [ Designated as safety issue: No ]
- Presence of vomiting [ Time Frame: 2 hours ] [ Designated as safety issue: No ]
- Use of rescue medications [ Time Frame: 2 hours ] [ Designated as safety issue: No ]Permitted per protocol 60 minutes after start if intravenous infusion.
- Sustained pain-free [ Time Frame: 25 hours ] [ Designated as safety issue: No ]No recurrence of headache within 24 hours if pain was completely eliminated (VAS = 0) prior to discharge.
- Sustained headache relief [ Time Frame: 24 hours ] [ Designated as safety issue: No ]No increase in headache by 33% on the VAS or 50% on the VAS if headache relief was initially achieved.
- Minimum clinically significant difference [ Time Frame: 2 hours ] [ Designated as safety issue: No ]
- "I would take the medication again" (Friedman, Bijur et al. 2010)
- "My headache is a bit better/worse"
- "My headache is a lot better/worse" (Powell, Kelly et al. 2001)
- Adverse events [ Time Frame: 2 hours ] [ Designated as safety issue: Yes ]All serious and non-serious adverse events including akathisia and dystonia.
|Study Start Date:||February 2012|
|Estimated Study Completion Date:||April 2014|
|Estimated Primary Completion Date:||April 2014 (Final data collection date for primary outcome measure)|
Experimental: Metoclopramide, Ketorolac
Drug: Ketorolac Tromethamine
Ketorolac 0.5 mg/kg (max 30 mg) IV
Other Names:Drug: Metoclopramide
Metoclopramide 0.2 mg/kg (max 10 mg) IV
Placebo Comparator: Metoclopramide, Placebo
Metoclopramide 0.2 mg/kg (max 10 mg) IV
Migraine headache is a painful condition of recurrent moderate to severe head pain associated with nausea, vomiting, photophobia, and phonophobia. The condition is highly prevalent and a significant community health problem with considerable impact on the health care system. To alleviate the pain and morbidity associated with a migraine attack, drug therapies are often employed including simple analgesics like ibuprofen and migraine-specific medications like sumatriptan. When these treatments fail or in severe, intractable cases, patients and families may present to the Emergency Department (ED).
Ketorolac in combination with metoclopramide or prochlorperazine was the most common multi-drug combination used in 36% of ED presentations for migraine across Canada in our national practice variation study. The scientific rationale for combining a non-selective non-steroidal anti-inflammatory drug (NSAID) with inhibition of both the cyclooxygenase (COX) 1 and 2 isoenzymes with other migraine therapies is enticing; however, no studies have specifically examined the relative efficacy of the practice. Why would the combination of a non-selective NSAID like ketorolac with other migraine therapies improve treatment outcomes? The benefit of multi-target combinations may be relate to the duration of the migraine and the multiple brain areas involved in sustained pain. It has long been recognized that patients who treat their migraine headaches early at the onset have a better response. The underlying mechanism for this phenomenon has now been identified. The initiation of migraine pain requires activation of the trigeminal (5th cranial nerve) nociceptive (pain) system. Activation of these sensory fibers within the arachnoid membrane on the surface of the brain produces the first and most common painful manifestation of migraine - the pulsatile headache. With each heartbeat, minor dilation of the cerebral blood vessels produces stretch and a painful activation of the trigeminal fibers known as peripheral sensitization. The second phase in the maintenance of a migraine attack over several hours is the sensitization of trigeminal pain pathways leading to higher brain centers known as central sensitization. The efficacy of medications like the triptans is greater early in the course of a migraine attack when there is only peripheral sensitization and before the onset of central sensitization. Non-selective NSAIDs like naproxen sodium and ketorolac may be uniquely effective in the reduction of central sensitization in the animal model of migraine and the reduction of migraine pain in adult patients late in the course of a migraine headache.
The population of patients in the ED is uniquely different from outpatients in that most have developed their migraine headache hours or days before presenting. In our practice variation study, the mean duration of the migraine prior to presenting to the ED was 2 days. Including an NSAID when treating a prolonged migraine in the ED may thus increase the therapeutic window and improve outcomes. While many Canadian ED physicians have adopted the practice of combining ketorolac with other migraine therapies, the gold standard assessment of efficacy and safety in a randomized clinical trial has not been applied.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01596166
|Contact: Lawrence Richer, MD, MSc||(780) firstname.lastname@example.org|
|Alberta Children's Hospital||Recruiting|
|Calgary, Alberta, Canada, T3B 6A8|
|Contact: Janie Williamson, RN 403-955-3186 Janie.Williamson@albertahealthservices.ca|
|Principal Investigator: David Johnson, MD|
|Stollery Children's Hospital||Recruiting|
|Edmonton, Alberta, Canada, T6G 2C8|
|Contact: Dory Sample, MSN, MPH (780) 248-5599 Dory.Sample@albertahealthservices.ca|
|Principal Investigator: Samina Ali, MD|
|Principal Investigator:||Lawrence P. Richer, MD, MSc||University of Alberta|