Clinical trial NCT03220958
Conditions: Post-Traumatic Headache
Sponsor: Montefiore Medical Center
Start date: 2017-08-01; Completion date: 2020-04-01
Enrollment: 160 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Nearly 1.5 million patients present to US emergency departments annually following head trauma. Headache is a frequent symptom of victims of head trauma. The purpose of this study is to see if an intravenous medication called metoclopramide can improve the symptoms of patients with acute post-traumatic headache.

Detailed description:

Arms: arm 1: Metoclopramide 20mg + diphenhydramine 25mg + 100cc normal saline, administered as an intravenous drip arm 2: Normal saline, administered as an intravenous drip
Interventions: intervention 1: Metoclopramide intervention 2: Diphenhydramine intervention 3: Normal saline
Intervention descriptions: intervention 1: Metoclopramide 20mg intervention 2: Diphenhydramine 25mg intervention 3: 100ml normal saline

Protocol documents:
Prot_SAP_002.pdf: 
PTH RCT. MCP versus placebo. 07112018 
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A randomized placebo controlled trial of IV metoclopramide for acute post-traumatic 
headache  
Protocol version date 07112018 
 
Nearly 1.5 million patients present to US 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. Post-traumatic headaches are thought to be likely to respond to the same 
parenteral medications as primary headaches, but this hypothesis has never been tested 
experimentally. We propose a randomized, double blind, placebo controlled study of 
metoclopramide for acute post-traumatic headache. Our primary hypothesis is that 
metoclopramide will improve headache pain more than placebo one hour after 
medication administration. Secondarily, we will determine whether metoclopramide is 
associated with persistent headache relief up to 48 hours, one week, and 30 days after 
medication administration. 
 
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. 
 
Pilot data. 
In an open label study of patients with post-traumatic headache conducted in the 
Montefiore EDs, 9 patients with moderate or severe post-traumatic headache were 
administered the medication regimen described in this protocol. 8 of the 9 patients 
reported no headache within two hours of receiving the medication. The remaining 
patient reported mild headache. During the 48 hours after medication administration, 
three of the nine patients relapsed and had headaches worse than mild. The only adverse 
event patients reported was drowsiness. Eight of the nine patients reported that they 
would want to receive the same medication regimen during a subsequent ED visit for 
headache. The one patient who would not want the same medication again said so 
attributed this response to medication-induced drowsiness. 
 
Methods. 
Overview. This will be a randomized, double blind, placebo-controlled study of IV 
metoclopramide for acute post-traumatic headache. This study will be conducted in two 
Montefiore EDs. This study will be reviewed by the Albert Einstein College of Medicine 
IRB and be registered online at http://clinicaltrials.gov. 
 


PTH RCT. MCP versus placebo. 07112018 
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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 a 
parenteral medication. 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 
 
Investigational medications: Interventions in each study arm are as follows: 
 
1) Active arm: Metoclopramide 20mg + diphenhydramine 25mg IV drip over 15 minutes. 
Diphenhydramine is co-administered to prevent subjective restlessness, a not infrequent 
side effect of higher doses of metoclopramide.(5)  
2) Placebo: Normal saline IV drip over 15 minutes  
 
Rationale for placebo. To the best of our knowledge, there are no published studies of 
treatment for acute post-traumatic headache. It is unknown if active intravenous treatment 
is more beneficial than normal saline alone. Therefore, there is a compelling rationale for 
a placebo-controlled study. Patients who have not experienced adequate headache relief 
one hour after treatment initiation will be offered rescue therapy. 
 
 
Assignment. Will be concealed. The research pharmacist will determine assignment 
based on a random number sequence at http://randomization.com. This random number 
sequence will be maintained in a secure location in the pharmacy, inaccessible to research 
staff or clinicians. 
Randomization. Randomization will occur in blocks of four based on a random number 
generator.  
Blinding. Patients, clinicians, and research personnel will be blinded. The pharmacist will 
stock the secured medication cabinet in the ED with sequentially numbered research 
packages. Each research package will contain two vials, one containing metoclopramide 
20mg in solution with normal saline or normal saline alone, the other containing 
diphenhydramine 25mg in solution with normal saline or normal saline alone. The 
metoclopramide and diphenhydramine solutions appear identical to normal saline. The 
research packages will be used in sequential order. 
Stratification. Subjects will be stratified by study site and baseline headache intensity. 
 


PTH RCT. MCP versus placebo. 07112018 
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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. The primary outcome is improvement in 0 to 10 pain score between 
medication administration and one hour later 
Secondary 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, 7 days, and 30 days 
 
Details of protocol. Patients who present to the Moses or Weiler 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. Masked medication will be 
obtained from the secured medication cabinet. The research associate will perform a 
baseline pain assessment. The ED nurse will then take the two vials containing 
metoclopramide, diphenhydramine, or normal saline alone, insert these vials into a 100cc 
bag of normal saline, and administer as an intravenous drip over 15 minutes. 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 and medical history.  Contact 
information will be verified. A specific time to perform the first follow-up phone call will 
be scheduled. Research personnel will ensure that study subjects have a way home and do 
not have to drive themselves. 
 


P T H R C T. M C P v ers us pl ac e b o.  0 71 1 2 0 1 8  
4  
F oll o w- u p p h o ne calls will be perf or me d 4 8 h o urs a n d 7 a n d 3 0 da ys after E D disc har ge. 
At t he first call, t he ne xt f oll o w - u p p h o ne call will be sc he d ule d. Atte m pts t o c o m plete 
t he f oll o w- u p calls s uccessf ull y will be ma de e ver y ei g ht h o urs u ntil dee m e d f utile.  
 
At t he 4 8- h o ur p h o ne call, t he f oc us will be assess me nts of pai n a n d ass oci ate d 
s y m pt o ms, a d vers e e ve nts, satisfacti o n wit h t he me dicati o n recei ve d, a n d use of res c ue 
me dicati o n. T he f o c us of t he se ve n da y p h o n e call will be t otal n u m ber of d a ys wit h 
hea dac he a n d ass ociate d s y m pt o ms si nce E D disc har ge, t he n ee d f or re p eat E D visits, 
healt hcar e pr o vi ders visite d, da ys of w or k misse d, a n d a d vers e me dicati o n effects.  
 
T he S C A T P C S S wi ll be assesse d at b ot h 4 8 h o urs, 7 da ys a n d 3 0 da ys. 
 
Baseli ne c o -variates  
1. Se verit y of i nitial tra u ma, as meas ure d b y pres e nce a n d d urati o n of l oss of 
c o nsci o us ness a n d a m n esia ( missi n g ti me) 
2. A n xiet y, as meas ur e d b y a n xiet y s cale  ( G A D-7)  
3. C o ncer n a b o ut ca use of hea dac he  (F o ur ite m Li kert: I pr o ba bl y di d n’t nee d t o see a 
d oct or b ut I wa nte d t o b e s ure; I’ m n ot s ure if I di d or di d n’t nee d t o see a d oct or; I 
pr o ba bl y nee d e d t o see a d oct or; I defi nitel y nee de d t o see a d oct or)  
4 Pers o nal a n d f a mil y  pri mar y h ea d ac he hist or y  
5. Patie nt’s assess me nt of lia bilit y ( n o o nes fa ult, patie nt’s fa ult, s o me o ne else’s fa ult) 
 
A nal ysis.  
Pri mar y o utc o m e. We will re p ort mea n o ne- h o ur i m pr o ve me nt i n eac h gr o u p wit h 
9 5 % CIs. We will cal c ulate bet wee n - gr o u p differe nce i n mea n o n e- h o ur i m pr o ve me nt a n d 
re p ort t his wit h 9 5 % CIs. If t he 9 5 % CI d o es n ot cr oss 0, t he res ult will be c o nsi dere d 
statisticall y si g nifica nt.  
Sec o n dar y o utc o me. We will re p ort fre q u e ncies of s ustai ne d hea dac he relief i n eac h 
gr o u p wit h 9 5 % CI. We will calc ulate t he bet w ee n gr o u p differe nce (a bs ol ute ris k 
re d ucti o n) a n d re p ort t his wit h 9 5 % CI. We will cal c ulate t he n u m ber n ee d e d t o treat a n d 
re p ort t his wit h 9 5 % CI. 
Ot her o utc o mes. Dic h ot o m o us o utc o mes will be re p orte d as fre q u e ncies wit h 9 5 % CI. 
Hea dac he d a ys a n d P C S S sc ore will be re p orte d as mea n wit h 9 5 % C I. Bet wee n gr o u p 
differe n ces will be calc ul ate d as a b o v e.  
 
Sa m ple size calc ulati o n: A re vie w of a rece nt mi grai ne trial i n v ol vi n g met o cl o pra mi de 
re veal e d a mea n i m pr o ve me nt i n 0 – 1 0 sc ore of 5. 1 a n d a sta n dar d de viati o n of 2. 8.( 6) 
Usi n g t hese v al ues a n d  ass u mi n g a n or mal distri b uti o n, a t w o-si de d = 0. 0 5, a n d a 
mi ni m u m cli nicall y  i m p orta nt differe nce bet wee n gr o u ps of 1. 3, we calc ulate d t he nee d 
f or 7 4 patie nts i n eac h gr o u p. We i nte n d t o e nr oll a n a d diti o nal 1 0 % t o acc o u nt f or 
pr ot oc ol vi olati o ns a n d missi n g data, gi vi n g a t otal sa m ple size of 1 6 2. 
 
Data c ollecti o n a n d pr ocessi n g. D ata ac q uisiti o n will be perf or me d usi n g R E D Ca p 
( Resear c h Electr o nic Dat a Ca pt ure), a sec ure, w e b- base d a p plicati o n desi g n e d 
s pecificall y t o s u p p ort data ca pt ure f or researc h st u dies. T he R E D Ca p 


PTH RCT. MCP versus placebo. 07112018 
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project  (http://project-redcap.org/) is an international project, with more than 70 
institutional partners from CTSA and GCRC funded institutions.  
 
Data monitoring committee and interim analysis. This committee will be headed by Dr. 
Polly Bijur, PhD, an epidemiologist and include Dr. Esses, MD, the director of the Moses 
ED. The committee will meet every month with the PI to monitor:  1) adverse events; and 
2) recruitment and enrollment. We will not perform an interim analysis as we wish to 
optimize the precision with which we report study results. 
 
Registration. The study will be registered at http://www.clinicaltrials.gov. 
 
Consent. Informed consent will be obtained after the patient is evaluated in 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. Both research associates and health care 
providers will participate in the consent process. Both will document their participation 
with a note in Epic and by signing the consent document. 
 
Pyxis procedures. The healthcare provider will place an order in Epic for the study 
medication. The order will trigger a specific pocket in Pyxis to open. The research 
associate and the clinical nurse will then complete the RA/RN checklist (Appendix). 
 
Description of orientation and education that providers receive about this study and about 
research procedures. This study in particular and research procedures in general are 
introduced during faculty meetings and reinforced with emails and Powerpoints. The PI 
then meets with providers in brief one-on-one sessions to describe these. Finally, the 
investigators and research associates discuss these during the in-shift briefs. 
 
 
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 will be performed 
on password-protected computers. Consent documents will be maintained in locked 
research cabinets in inaccessible areas. Only study personnel will have access to the data 
and consent documents. 
 


PTH RCT. MCP versus placebo. 07112018 
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PTH RCT. MCP versus placebo. 07112018 
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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. 
6. 
Friedman BW, Mistry B, West JR, Wollowitz A. The association between 
headache and elevated blood pressure among patients presenting to an ED. 
Am J Emerg Med. 2014;32(9):976-81. 
 
 
 


PTH RCT. MCP versus placebo. 07112018 
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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  
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