Clinical trial NCT03056352
Conditions: Post-Traumatic Headache
Sponsor: Montefiore Medical Center
Start date: 2017-03-01; Completion date: 2017-08-15
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Post-traumatic headache is common. We are determining short and longer-term outcomes among patients treated for post-traumatic headache with IV metoclopramide.

Detailed description:

Arms: arm 1: Metoclopramide 20mg + diphenhydramine 25mg administered intravenously over 15 minutes
Interventions: intervention 1: Metoclopramide intervention 2: Diphenhydramine
Intervention descriptions: intervention 1: Intravenous medication drip intervention 2: Intravenous medication drip

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
Metoclopramide for Post-Traumatic Headache 
A Pilot Study 
 
 
 
 
 
 
 
 
 
NCT#: NCT03056352 
Protocol ID: 2017-7511 
Version Date: 02/16/2017 
 
 
 
 
 
 
 
 
 
 
 
Benjamin W. Friedman, MD 
Professor and vice-chair for clinical investigation 
Department of Emergency Medicine 
Montefiore Medical Center 
Albert Einstein College of Medicine 
 


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A pilot study of IV metoclopramide for acute post-traumatic headache  
 
Nearly 1.5 million patients present to US emergency departments EDs annually following 
head trauma.(1) Headache is a frequent symptom of victims of trauma and may take the 
form of either migraine or tension-type headache. (2) For most patients, post-traumatic 
headaches will resolve after several months, though up to ¼ will develop a persistent 
headache syndrome.(2) Post-traumatic headaches are believed to respond to the same 
parenteral medications as primary headaches, but this hypothesis has never been tested 
experimentally. We propose a series of clinical investigations examining the role of IV 
metoclopramide for acute post-traumatic headache. Our hypothesis is that 
metoclopramide will improve headache pain more than placebo one hour, 48 hours and 
one week after medication administration. As a precursor to a definitive study, we intend 
to perform an open-label pilot study to determine the feasibility of this line of 
investigation.  
 
It is not yet understood why anti-dopaminergic medications are effective treatment for 
acute headache, but there is a substantial evidence base supporting efficacy of this class 
of medication for headache, regardless of whether the headache is migraine,(3) or 
tension-type(4) headache. Also, when used for headache, this medication is generally 
well-tolerated; serious adverse events have not been reported in this population. Given 
this track record of successful use in primary headache disorders, we believe this 
medication is appropriate for use in this initial study of parenteral treatment for post-
traumatic headache. 
 
Methods 
Overview. This will be a non-randomized, open-label study of IV metoclopramide for 
acute post-traumatic headache. Patients will be enrolled during a visit to one of two 
Montefiore EDs and followed by telephone 48 hours and 7 days after the ED visit.  
 
Population of interest: Included patients will be adults who meet International 
Classification of Headache Disorders criteria for acute post-traumatic headache. These 
are as follows: 
-Traumatic injury to the head has occurred 
- Headache has developed within 7 days of injury to the head 
-Headache is not better accounted for by another diagnosis (eg, previous history of 
migraine or tension-type headache) 
 
The headache must be rated as moderate or severe in intensity at the time of initial 
evaluation. The plan of the attending emergency physician must include treatment with 
parenteral metoclopramide. Patients will be excluded if more than ten days have elapsed 
since the head trauma, if the headache has already been treated with an anti-dopaminergic 
medication, or for medication contra-indications including pheochromocytoma, seizure 
disorder, Parkinson’s disease, use of MAO inhibitors, and use of anti-rejection transplant 
medications. Patients will be excluded for pregnancy. 
 
Study setting: This study will be conducted in the Moses and Einstein EDs 


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Investigational medications: Metoclopramide 20mg IV drip over 15 minutes + 
diphenhydramine 25mg IV drip over 15 minutes. Diphenhydramine is co-administered to 
prevent subjective restlessness.(5)  
 
Measures 
Numerical Rating Scale for pain. This is a 0 to 10 verbal rating scale on which 0 signifies 
no pain and 10 signifies the worst pain imaginable.  
International Headache Society pain scale. Headache is described as severe, moderate, 
mild, or none 
Satisfaction scale. Patients are asked if they would want to receive the same medication 
during a subsequent visit to the ED for post-traumatic headache 
Overall sense of wellbeing. Patients are asked to report their overall health since before 
their injury as better, same, or worse 
The Sport Concussion Assessment Tool (SCAT) Post Concussion Symptom Scale 
(PCSS). On this validated instrument, patients rate 25 symptoms on a 0 to 6 scale. 
(Appendix) 
 
Primary outcome  
Headache relief for 48 hours—Achieving a headache intensity of mild or none in the ED 
without use of rescue medication and maintaining that level for 48 hours. 
 
Other outcomes  
1) Use of additional medication in the ED for headache 
2) Use of additional medication in the ED for associated symptoms 
3) Achieving headache freedom in the ED without use of additional medication for 
headache 
4) Satisfaction with the medication, measured at the 48 hour follow-up phone call 
5) Number of days with headache during the week after ED discharge 
6) Return visits to the ED over the week after discharge 
7) SCAT PCSS at 48 hours and 7 days 
 
Details of protocol  
Patients who present to either of the study EDs with an acute headache will be referred by 
the attending emergency physician to the research staff for enrollment. Eligibility will be 
ascertained by research associates and verified by the site investigator. Capacity to 
consent to participate in this study will be assessed by the attending emergency physician 
and specifically documented. The research associate will perform a baseline pain 
assessment. The ED nurse will then administer the research medication as described 
above. The research associates will return every 30 minutes to perform an assessment of 
headache, associated features, and adverse events. The use of rescue medications to treat 
persistent pain will also be recorded. Prior to discharge, research associates will ascertain 
key socio-demographics and pertinent features of the headache history.  Contact 
information will be verified by calling the number given at the time of acquisition in the 
ED. A specific time to perform the first follow-up phone call will be scheduled.  
 


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Follow-up phone calls will be performed 48 hours and 7 days after ED discharge. At the 
first call, the next follow-up phone call will be scheduled. Attempts to complete the 
follow-up calls successfully will be made every eight hours until deemed futile. At this 
point, questionnaires will be sent by express courier, and failing this, the investigator will 
perform a home visit.  
 
 At the 48-hour phone call, the focus will be assessments of pain and associated 
symptoms, adverse events, satisfaction with the medication received, and use of rescue 
medication. The focus of the seven day phone call will be total number of days with 
headache and associated symptoms since ED discharge, the need for repeat ED visits, 
healthcare providers visited, days of work missed, and adverse medication effects.  
 
Baseline co-variates 
1. Severity of initial trauma, as measured by presence and duration of loss of 
consciousness and amnesia (missing time) 
2. Anxiety, as measured by anxiety scale (GAD-7) 
3. Concern about cause of headache (Four item Likert: I probably didn’t need to see a 
doctor but I wanted to be sure; I’m not sure if I did or didn’t need to see a doctor; I 
probably needed to see a doctor; I definitely needed to see a doctor)  
4 Personal and family primary headache history 
5. Patient’s assessment of liability (no one’s fault, patient’s fault, someone else’s fault) 
 
Sample size: We intend to enroll up to 20 patients. We will review data after each group 
of five patients to determine whether there is compelling data to proceed with a definitive 
study.  
 
Analysis  
The primary purpose of this study is to determine whether there is a compelling rationale 
to proceed with a definitive study. We will analyze the data after each group of five 
patients have been enrolled. If 0 of the initial five patients achieve the primary outcome, 
we will halt this line of investigation. After 10 patients have been enrolled, we will use 
the threshold of 40% response (48 hour sustained relief) to determine whether or not to 
proceed with the definitive study. We intend to continue enrollment until 10 patients have 
provided complete outcome data (may require up to 20 patients). We also intend to 
continue enrollment beyond 10 patients in this pilot study if study instruments require 
refinement or if there is discrepancy between primary and secondary outcomes. 
 
Data collection and processing  
Data acquisition will be performed using REDCap (Research Electronic Data Capture), a 
secure, web-based application designed specifically to support data capture for research 
studies. The REDCap project  (http://project-redcap.org/) is an international project, with 
more than 70 institutional partners from CTSA and GCRC funded institutions. Paper 
consent documents will be maintained in locked research cabinets. 
 
 
 


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Consent  
Informed consent will be obtained when patients present to the ED.  As part of our 
consent process, we will offer to help patients call a family member or friend and discuss 
the study with them if they wish.  We will also have the patient’s attending physician 
confirm that the patient has the capacity to consent to participate in the study at the time 
they are asked to provide consent. 
 
Risks/Benefits 
Anti-dopaminergics such as metoclopramide can cause extra-pyramidal side effects 
including tardive dyskinesia. Irreversible extra-pyramidal symptoms have never been 
reported after one intravenous dose of metoclopramide. The investigational medication 
can also cause a variety of nuisance side effects including dizziness, drowsiness, and 
palpitations. As with any clinical study, there is a risk that the patient’s personal 
identifiers and private health data may be seen by non-study personnel. It is clear that a 
great many patients continue to suffer from headache after ED discharge. This protocol is 
specifically designed to inform the ED-based treatment of acute post-traumatic headache. 
 
Data Storage & Confidentiality 
Data will be stored and maintained securely in REDCap. Data analysis initially de-
identifies patients, and is done only on password-protected computers behind an 
institutional firewall, protected with professionally maintained anti-viral software. 
Consent documents will be maintained in locked research cabinets in inaccessible areas. 
Only study personnel will have access to the data and consent documents. 
 
 
 


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References 
1. 
Blyth BJ, Bazarian JJ. Traumatic alterations in consciousness: traumatic brain 
injury. Emergency medicine clinics of North America. 2010;28(3):571‐94. 
2. 
Seifert TD, Evans RW. Posttraumatic headache: a review. Current pain and 
headache reports. 2010;14(4):292‐8. 
3. 
Orr SL, Friedman BW, Christie S, Minen MT, Bamford C, Kelley NE, et al. 
Management of Adults With Acute Migraine in the Emergency Department: 
The American Headache Society Evidence Assessment of Parenteral 
Pharmacotherapies. Headache. 2016;56(6):911‐40. 
4. 
Weinman D, Nicastro O, Akala O, Friedman BW. Parenteral treatment of 
episodic tension‐type headache: a systematic review. Headache. 
2014;54(2):260‐8. 
5. 
Friedman BW, Bender B, Davitt M, Solorzano C, Paternoster J, Esses D, et al. A 
randomized trial of diphenhydramine as prophylaxis against 
metoclopramide‐induced akathisia in nauseated emergency department 
patients. Annals of emergency medicine. 2009;53(3):379‐85. 
 
 
 


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Post Concussion Symptom Scale  
 
0=none, 6= severe 
 
Headache 0 1 2 3 4 5 6  
“Pressure in head” 0 1 2 3 4 5 6  
Neck Pain 0 1 2 3 4 5 6  
Balance problems or dizzy 0 1 2 3 4 5 6  
Nausea or vomiting 0 1 2 3 4 5 6  
Vision problems 0 1 2 3 4 5 6  
Hearing problems / ringing 0 1 2 3 4 5 6  
“Don’t feel right” 0 1 2 3 4 5 6  
Feeling “dinged” or “dazed” 0 1 2 3 4 5 6  
Confusion 0 1 2 3 4 5 6  
Feeling slowed down 0 1 2 3 4 5 6  
Feeling like "in a fog" 0 1 2 3 4 5 6  
Drowsiness 0 1 2 3 4 5 6  
Fatigue or low energy 0 1 2 3 4 5 6  
More emotional than usual 0 1 2 3 4 5 6  
Irritability 0 1 2 3 4 5 6  
Difficulty concentrating 0 1 2 3 4 5 6  
Difficulty remembering 0 1 2 3 4 5 6  
 
(follow up symptoms only)  
Sadness 0 1 2 3 4 5 6  
Nervous or Anxious 0 1 2 3 4 5 6  
Trouble falling asleep 0 1 2 3 4 5 6  
Sleeping more than usual 0 1 2 3 4 5 6  
Sensitivity to light 0 1 2 3 4 5 6  
Sensitivity to noise 0 1 2 3 4 5 6  
Other: _______________ 0 1 2 3 4 5 6