Intravenous Ketorolac and Metoclopramide for Pediatric Migraine in the Emergency Department (EDMigraine-4)

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2013 by University of Alberta
Sponsor:
Collaborator:
Canadian Institutes of Health Research (CIHR)
Information provided by (Responsible Party):
University of Alberta
ClinicalTrials.gov Identifier:
NCT01596166
First received: May 8, 2012
Last updated: September 9, 2013
Last verified: August 2013
  Purpose

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.


Condition Intervention Phase
Probable Migraine
Migraine With Aura
Migraine Without Aura
Drug: Ketorolac Tromethamine
Drug: Metoclopramide
Phase 4

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by University of Alberta:

Primary Outcome Measures:
  • Mean reduction in pain intensity [ Time Frame: 2 hours ] [ Designated as safety issue: No ]
    Measured on Visual Analogue Scale (VAS).


Secondary Outcome Measures:
  • 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 ]
    1. "I would take the medication again" (Friedman, Bijur et al. 2010)
    2. "My headache is a bit better/worse"
    3. "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.


Estimated Enrollment: 50
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)
Arms Assigned Interventions
Experimental: Metoclopramide, Ketorolac
  1. 10 mL/kg IV 0.9% sodium chloride
  2. Metoclopramide 0.2 mg/kg (max 10 mg) IV
  3. Ketorolac 0.5 mg/kg (max 30 mg) IV
Drug: Ketorolac Tromethamine
Ketorolac 0.5 mg/kg (max 30 mg) IV
Other Names:
  • Toradol
  • 74103-07-4
Drug: Metoclopramide
Metoclopramide 0.2 mg/kg (max 10 mg) IV
Other Names:
  • Maxeran
  • Reglan
  • 364-62-5
Placebo Comparator: Metoclopramide, Placebo
  1. 10 mL/kg IV 0.9% sodium chloride
  2. Metoclopramide 0.2 mg/kg (max 10 mg) IV
  3. Placebo (normal saline)
Drug: Metoclopramide
Metoclopramide 0.2 mg/kg (max 10 mg) IV
Other Names:
  • Maxeran
  • Reglan
  • 364-62-5

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   6 Years to 17 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

A patient is legible to participate in this study if they meet the following criteria:

  1. Patient is between 6 and 17 years of age inclusive
  2. Treatment with usual therapy at home or at least one dose of oral ibuprofen or acetaminophen has not provided satisfactory relief
  3. Intravenous therapy is indicated in the opinion of the treating ED physician
  4. Patient has a history of migraine as defined by the International Classification of Headache Disorders - 2nd edition (Appendix 1) and meets the following criteria:

    1. During headache, at least 1 of the following: nausea and/or vomiting; two of five symptoms (photophobia, phonophobia, difficulty thinking, lightheadedness, or fatigue). Symptoms may be inferred from patient's behavior.
    2. Headache has at least 2 of the following characteristics: bifrontal/bitemporal or unilateral location; pulsating/throbbing quality; moderate or severe pain intensity; aggravation by or causing avoidance of routine physical activity. Symptoms may be inferred from patient's behavior.

Exclusion Criteria:

A patient is not eligible to participate in the study if any of the following criteria apply:

  1. Patient has a contraindication to the use of metoclopramide or ketorolac in the opinion of the ED physician
  2. Patient has a ventriculoperitoneal shunt
  3. Patient has a fever (temperature > 38.5 oC)
  4. Patient has meningismus or clinical suspicion of meningitis in the opinion of the ED physician
  5. Patient has a history of head trauma causing headache in the last 1 week prior to presentation to the ED
  6. Patient is unable to complete the efficacy assessments (e.g. language barrier)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01596166

Contacts
Contact: Lawrence Richer, MD, MSc (780) 248-5568 lricher@ualberta.ca

Locations
Canada, Alberta
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         
Sponsors and Collaborators
University of Alberta
Canadian Institutes of Health Research (CIHR)
Investigators
Principal Investigator: Lawrence P. Richer, MD, MSc University of Alberta
  More Information

No publications provided

Responsible Party: University of Alberta
ClinicalTrials.gov Identifier: NCT01596166     History of Changes
Other Study ID Numbers: EDMIGR-004-01
Study First Received: May 8, 2012
Last Updated: September 9, 2013
Health Authority: Canada: Health Canada

Keywords provided by University of Alberta:
migraine
pediatric
childhood
emergency department
ketorolac
metoclopramide
intravenous

Additional relevant MeSH terms:
Migraine Disorders
Migraine with Aura
Migraine without Aura
Emergencies
Disease Attributes
Pathologic Processes
Headache Disorders, Primary
Headache Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Metoclopramide
Ketorolac Tromethamine
Ketorolac
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Gastrointestinal Agents
Dopamine Antagonists
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents

ClinicalTrials.gov processed this record on August 28, 2014