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

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ClinicalTrials.gov Identifier: NCT01596166
Recruitment Status : Completed
First Posted : May 10, 2012
Last Update Posted : January 26, 2015
Canadian Institutes of Health Research (CIHR)
Information provided by (Responsible Party):
University of Alberta

Brief Summary:
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 or disease Intervention/treatment Phase
Probable Migraine Migraine With Aura Migraine Without Aura Drug: Ketorolac Tromethamine Drug: Metoclopramide Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 56 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Efficacy of Combination Therapy With Intravenous Ketorolac and Metoclopramide for Pediatric Migraine Therapy in the Emergency Department
Study Start Date : February 2012
Actual Primary Completion Date : April 2014
Actual Study Completion Date : April 2014

Arm Intervention/treatment
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

Primary Outcome Measures :
  1. Mean reduction in pain intensity [ Time Frame: 2 hours ]
    Measured on Visual Analogue Scale (VAS).

Secondary Outcome Measures :
  1. Pain freedom [ Time Frame: 2 hours ]

  2. Headache relief - 33 [ Time Frame: 2 hours ]
    Defined as a 33% reduction on the VAS.

  3. Headache relief - 50 [ Time Frame: 2 hours ]
    Defined as a 50% reduction on the VAS

  4. Presence of nausea [ Time Frame: 2 hours ]
  5. Presence of vomiting [ Time Frame: 2 hours ]
  6. Use of rescue medications [ Time Frame: 2 hours ]
    Permitted per protocol 60 minutes after start if intravenous infusion.

  7. Sustained pain-free [ Time Frame: 25 hours ]
    No recurrence of headache within 24 hours if pain was completely eliminated (VAS = 0) prior to discharge.

  8. Sustained headache relief [ Time Frame: 24 hours ]
    No increase in headache by 33% on the VAS or 50% on the VAS if headache relief was initially achieved.

  9. Minimum clinically significant difference [ Time Frame: 2 hours ]
    1. "I would take the medication again"
    2. "My headache is a bit better/worse"
    3. "My headache is a lot better/worse"

  10. Adverse events [ Time Frame: 2 hours ]
    All serious and non-serious adverse events including akathisia and dystonia.

Information from the National Library of Medicine

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Ages Eligible for Study:   6 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01596166

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Canada, Alberta
Alberta Children's Hospital
Calgary, Alberta, Canada, T3B 6A8
Stollery Children's Hospital
Edmonton, Alberta, Canada, T6G 2C8
Sponsors and Collaborators
University of Alberta
Canadian Institutes of Health Research (CIHR)
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Principal Investigator: Lawrence P. Richer, MD, MSc University of Alberta
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Responsible Party: University of Alberta
ClinicalTrials.gov Identifier: NCT01596166    
Other Study ID Numbers: EDMIGR-004-01
First Posted: May 10, 2012    Key Record Dates
Last Update Posted: January 26, 2015
Last Verified: January 2015
Keywords provided by University of Alberta:
emergency department
Additional relevant MeSH terms:
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Migraine Disorders
Migraine without Aura
Migraine with Aura
Disease Attributes
Pathologic Processes
Headache Disorders, Primary
Headache Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Ketorolac Tromethamine
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Autonomic Agents
Gastrointestinal Agents
Dopamine D2 Receptor Antagonists
Dopamine Antagonists