Abstract
Background
Headache is a frequent complaint among the 1.4 million patients who present to US emergency departments (ED) annually following trauma to the head. There are no evidence-based treatments of acute post-traumatic headache.
Methods
This was an ED-based, prospective study of intravenous (IV) metoclopramide 20 mg + diphenhydramine 25 mg for acute post-traumatic headache. Patients who presented to our EDs with a moderate or severe headache meeting international criteria were enrolled and followed by telephone 2 and 7 days later. The primary outcome was “sustained headache relief” (headache level less than “moderate” in the ED, no additional headache medication, and no relapse to headache worse than “mild”). We also gathered data on associated symptomotology using the validated Post Concussion Symptom Scale (PCSS).
Results
21 patients were enrolled. Twelve of 20 (60%) patients with available follow-up data reported sustained headache relief. All but one of the 21 enrolled patients (95%) reported improvement of headache to no worse than mild. Seven of 19 (37%) patients with available data reported moderate or severe headache during the 48 h after ED discharge. One week later, 5/19 patients reported experiencing headaches “frequently” or “always”. The mean Post Concussion Symptom Score improved from 47.5 (SD 29.4) before treatment to 10.9 (SD 14.8) at the time of ED discharge and 11.4 (SD 21.4) at one week after treatment.
Conclusion
IV metoclopramide 20 mg + diphenhydramine 25 mg is an effective and well-tolerated medication regimen for patients presenting to the ED with acute post-traumatic headache, though 1/3 of patients report headache relapse after ED discharge and 1/4 of patients report persistent headaches one week later.
Keywords: Post-traumatic headache, Emergency department, Metoclopramide, Diphenhydramine
1. Background
Nearly 1.4 million patients present to United States emergency departments (EDs) annually following head trauma [1]. Head trauma victims frequently report headache, along with other symptoms including dizziness, nausea, and disturbances in memory and concentration [2]. For most patients, post-traumatic headaches will resolve, though approximately 20% may develop a persistent headache syndrome.
Post-traumatic headaches commonly share descriptive characteristics and associated symptoms of the two most prevalent categories of primary headache—tension-type headache or migraine [2]. Because of this, they are often treated with the same medications as the primary headaches. However, we were unable to identify an evidence base to guide treatment of acute post-traumatic headache. In this open-label study, we sought to assess the efficacy of IV metoclopramide plus diphenhydramine for treatment of acute post-traumatic headache. This parenteral treatment regimen has been shown to be efficacious for both acute migraine [3] and acute tension-type headache [4]. Our hypothesis was that IV metoclopramide plus diphenhydramine would improve headache pain one hour, 48 h and one week after medication administration.
2. Methods
2.1. Study design and setting
This was a prospective, open-label study of IV metoclopramide + diphenhydramine for patients presenting to an ED with acute post-traumatic headache. Short-term outcomes were assessed in the ED. The post-ED course was determined through structured telephone interview at 48 h and 7 days. The Montefiore Medical Center IRB approved this protocol. Written consent was obtained from all participants.
We performed this study in two EDs of Montefiore Medical Center, in the Bronx, NY. Salaried, trained, fluently bilingual (English and Spanish) research associates staffed the ED 24 h per day, seven days per week during the enrollment period. Enrollment occurred during a four month period beginning in March 2017.
2.2. Selection of participants
Adult patients were eligible for this study if they presented to the ED for treatment of moderate to severe post-traumatic headache. To determine if patients were eligible, we used the International Classification of Headache Disorders (ICHD) 3-beta criteria for acute post-traumatic headache [5]. The criteria are as follows:
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Traumatic injury to the head has occurred
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Headache has developed within 7 days of injury to the head
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Headache is not more consistent with an alternative diagnosis (e.g., pre-existing migraine or tension-type headache)
Individuals could only be enrolled once. We excluded patients from this study if more than ten days elapsed since the head trauma, or the headache had already been treated with an anti-dopaminergic medication, and for pregnancy or medication contraindications.
2.3. Intervention
Subjects were treated with metoclopramide 20 mg plus diphenhydramine 25 mg, administered as an intravenous drip over 15 min.
2.4. Measures
Ordinal pain scale. Headache is described as severe, moderate, mild, or none
Headache functional scale. Functionality is described as severely impaired (can't get out of bed); moderately impaired (great deal of difficulty doing what I usually do); mildly impaired (some difficulty doing what I usually do); or not impaired
Headache frequency. Patients are asked to describe the frequency of their headaches as never, rarely, sometimes, often, or always.
Satisfaction scale. Patients were asked if they would want to receive the same medication during a subsequent visit to the ED for post-traumatic headache
The Sport Concussion Assessment Tool (SCAT) Post Concussion Symptom Scale (PCSS). On this validated instrument, patients rated 22 symptoms on a 0 to 6 scale (Appendix A).
Research associates performed a baseline pain assessment and a post-concussive symptom scale. ED nurses then administered the research medications. Research associates returned every 60 min to perform an assessment of headache, associated features, and adverse events. The use of rescue medications to treat persistent pain was also recorded. Following treatment and prior to discharge, research associates ascertained key socio-demographics, further description of the headache, and re-administered the post-concussive symptom scale.
Follow-up phone calls were performed 48 h and 7 days after ED discharge. During the 48-hour phone call, research associates assessed pain and associated symptoms, adverse events, satisfaction with the medication received, and use of rescue medication. The focus of the seven day phone call was total number of days with headache and associated symptoms since ED discharge. The post-concussive symptom scale was re-administered at 7 days.
2.5. Outcomes
The primary outcome was sustained headache relief for 48 h, defined as achieving a headache intensity of “mild” or “none” in the ED without use of rescue medication and maintaining that level for 48 h.
Other outcomes include:
Use of rescue medication in the ED for headache or associated symptoms
Headache intensity 1 and 2 h after medication administration, and during the 48 h after ED discharge
Functionality 2 h after medication administration and during the 48 h after ED discharge
Satisfaction with the medication
Number of days with headache during the 7 days following ED discharge
Return visits to healthcare providers
Post-concussive symptom scale post-treatment and 7 days after the ED visit.
2.6. Analysis
We performed descriptive analyses. Continuous outcomes are reported as mean with standard deviation or median with interquartile range, as appropriate. Dichotomous outcomes are reported as frequency (percent).
3. Results
21 patients were enrolled (Fig. 1). Of these, 19 were successfully followed 48 h and one week later. Baseline characteristics of these patients are presented in Table 1. Severe pain and functional disability were common features of patients at initial presentation to the emergency department. The most frequent cause of trauma was trip and fall. The majority of headaches were described as pulsating, pounding or throbbing. Every patient but one received a head CT in the ED (Table 1).
Fig. 1.
Flow diagram of patient participation.
Table 1.
Baseline characteristics.
| Variable | Value |
|---|---|
| Mean age in years (SD) | 45 (18) |
| Sex | |
| Men | 5 (24%) |
| Women | 16 (76%) |
| Pain at baseline | |
| Moderate | 5 (24%) |
| Severe | 16 (76%) |
| Functionality | |
| I can do my normal daily activities | 0 (0%) |
| I've been having a little bit of difficulty doing what I usually do | 5 (24%) |
| I've been having a great deal of difficulty doing what I usually do | 13 (62%) |
| I can't get out of bed | 3 (14%) |
| Median duration of headache, hours (IQR) | 24 (4, 72) |
| Mechanism of injury | |
| Trip/fall | 9 (43%) |
| Impacted stationary object | 4 (19%) |
| Projectile | 4 (19%) |
| Assault | 3 (14%) |
| Automobile accident | 1 (5%) |
| Headache description | |
| Pounding/pulsating/throbbing | 13 (62%) |
| Tightness/pressure/squeezing | 12 (57%) |
| Burning | 1 (5%) |
| Laterality | |
| Left | 2 (10%) |
| Right | 4 (19%) |
| Bilateral | 15 (71%) |
| Pain reported at site other than head or face | |
| Yes | 7 (33%) |
| No | 14 (67%) |
| Laceration requiring repair | |
| Yes | 0 (0%) |
| No | 21 (100%) |
| Took medication prior to presentation at ED | |
| Yes | 15 (71%) |
| No | 6 (29%) |
| Current use of anti-platelet or anti-coagulant medication | |
| Yes | 2 (10%) |
| No | 19 (90%) |
| Head CT in ED | |
| Yes | 20 (95%) |
| No | 1 (5%) |
Values are in n (%) unless otherwise stated. Participants were allowed to report more than one headache descriptor.
In the emergency department 1 h after treatment with metoclopramide plus diphenhydramine, 15 patients (71%) reported headache relief—that is, a reduction in pain to mild or none—and improved functionality (Table 2). By 2 h, all but one patient (95%) reported headache relief. Rescue medication was administered to two of the patients, one of whom was administered morphine for pain and the other diazepam for associated symptoms.
Table 2.
In-ED outcomes.
| Variable | |
|---|---|
| Pain at 1 h | |
| None | 8 (38%) |
| Mild | 7 (33%) |
| Moderate | 5 (24%) |
| Severe | 1 (5%) |
| Pain at 2 h | |
| None | 12 (57%) |
| Mild | 8 (38%) |
| Moderate | 1 (5%) |
| Severe | 0 (0%) |
| Functionality at 2 h | |
| I could do my normal daily activities | 15 (71%) |
| I'd have a little bit of difficulty doing what I usually do | 5 (24%) |
| I'd have a great deal of difficulty doing what I usually do | 1 (5%) |
| I can't get out of bed | 0 (0%) |
| Rescue medications | |
| Yes | 2 (10%)a |
| No | 19 (90%) |
Values are in n (%) unless otherwise stated.
One of these rescue medications was diazepam, which was used for associated symptoms.
At 48 h, slightly more than 1/3 of patients reported moderate or severe headache, although the vast majority of patients reported little to no difficulty performing usual activities (Table 3). Sustained headache relief–achieving a headache level of “mild” or “none” in the ED without rescue medication and not relapsing to a headache level worse than “mild”–was reported by 55% (11 of 20) of patients. If diazepam is not counted as a rescue medication, then the rate of sustained headache relief was 12/20 (60%). Of the two patients lost to followup, one required rescue medication in the ED and therefore can be counted as an outcome failure. Of 7 patients who reported other injuries in addition to head trauma, one was lost to follow-up. Two of the remaining six (33%) reported sustained headache relief.
Table 3.
48 hour follow up.
| Variable | Value |
|---|---|
| Headache | |
| None | 7 (37%) |
| Mild | 5 (26%) |
| Moderate | 4 (21%) |
| Severe | 3 (16%) |
| Functional disability | |
| I could do my normal daily activities | 12 (63%) |
| I'd have a little bit of difficulty doing what I usually do | 5 (26%) |
| I'd have a great deal of difficulty doing what I usually do | 1 (5%) |
| I can't get out of bed | 1 (5%) |
| Headache frequency since discharge | |
| Never/rarely | 10 (53%) |
| Sometimes | 3 (16%) |
| Often/always | 6 (32%) |
| Measure of satisfaction | |
| Would not take medication again | 2 (11%) |
| Would take medication again | 16 (84%) |
| Not sure | 1 (5%) |
Values are in n (%) unless otherwise stated.
At one week follow-up, more than 1/4 of patients reported that, during the week since ED discharge, they experienced headache “frequently” or “always” (Table 4). Four patients (21%) reported visiting a healthcare provider due to headaches since ED discharge.
Table 4.
1 week follow up.
| Variable | Value |
|---|---|
| Median number of days with headache since discharge (IQR) | 2 (0, 4) |
| Headache frequency since discharge | |
| Never/rarely | 10 (53%) |
| Sometimes | 4 (21%) |
| Often/always | 5 (26%) |
| Functional disability | |
| I've been doing my normal daily activities | 15 (79%) |
| I've had a little bit of difficulty doing what I usually do | 3 (16%) |
| I've have a great deal of difficulty doing what I usually do | 1 (5%) |
| I can't get out of bed | 0 (0%) |
| Use of headache medication since discharge | |
| No | 10 (53%) |
| Yes | 9 (47%) |
| Subsequent visit to healthcare provider | |
| No | 15 (79%) |
| Yes | 4 (21%) |
Values are in n (%) unless otherwise stated.
Patients were asked about adverse events at two time points, 1 h after medication administration, and 48 h after discharge. At 1 h post-treatment, no adverse events were reported. At 48 h, two patients (11%) reported sleepiness.
The mean PCSS score improved from 47.5 (SD 29.4) before treatment to 10.9 (SD 14.8) at discharge and 11.4 (SD 21.4) at one week after treatment. In general, prior to treatment, patients most frequently complained of headache, head pressure, and not feeling right. There were marked improvements in these PCSS-scored variables during the week after treatment (Table 5, Fig. 2).
Table 5.
Post-concussive Symptom Scores reported as median (interquartile range).
| Symptom | Baseline | ED discharge | 1 week follow up |
|---|---|---|---|
| Headache | 5 (4, 6) | 0 (0, 2) | 0 (0, 2) |
| Pressure in head | 5 (3, 6) | 0 (0, 1) | 0 (0, 1) |
| Neck pain | 0 (0, 6) | 0 (0, 2) | 0 (0, 3) |
| Nausea or vomiting | 3 (0, 5) | 0 (0, 0) | 0 (0, 0) |
| Dizziness | 3 (0, 4) | 0 (0, 0) | 0 (0, 0) |
| Blurred vision | 0 (0, 3) | 0 (0, 0) | 0 (0, 0) |
| Balance problems | 0 (0, 3) | 0 (0, 0) | 0 (0, 0) |
| Photosensitivity | 2 (0, 6) | 0 (0, 2) | 0 (0, 0) |
| Phonosensitivity | 0 (0, 5) | 0 (0, 0) | 0 (0, 0) |
| Feeling slowed down | 2 (0, 4) | 0 (0, 2) | 0 (0, 0) |
| Feeling in a fog | 2 (0, 4) | 0 (0, 0) | 0 (0, 0) |
| Not feeling right | 4 (1, 6) | 0 (0, 2) | 0 (0, 0) |
| Difficulty concentrating | 3 (0, 5) | 0 (0, 0) | 0 (0, 0) |
| Difficulty remembering | 0 (0, 3) | 0 (0, 0) | 0 (0, 0) |
| Fatigue | 2 (0, 5) | 0 (0, 2) | 0 (0, 0) |
| Confusion | 0 (0, 3) | 0 (0, 0) | 0 (0, 0) |
| Drowsiness | 0 (0, 3) | 0 (0, 2) | 0 (0, 0) |
| Difficulty falling asleep | 0 (0, 4) | 0 (0, 0) | 0 (0, 0) |
| Emotional | 0 (0, 1) | 0 (0, 0) | 0 (0, 0) |
| Irritable | 0 (0, 4) | 0 (0, 0) | 0 (0, 0) |
| Sadness | 0 (0, 2) | 0 (0, 0) | 0 (0, 0) |
| Nervousness | 0 (0, 3) | 0 (0, 0) | 0 (0, 0) |
| Sum score | 38 (22, 74) | 4 (0, 17) | 2 (0, 10) |
Fig. 2.
Mean scores of Post-Concussion Symptom Score variables at three time points.
4. Discussion
In this prospective, ED-based, open label study, IV metoclopramide 20 mg plus diphenhydramine 25 mg proved to be a modestly effective treatment for patients with acute post-traumatic headache. The treatment regimen provided almost every patient with acute relief, though about 1/3 reported headache relapse within 48 h. These medications restored most patients to normal functionality and eliminated other concussion symptoms. Few adverse medication effects were reported. However, about one quarter of the cohort reported frequent headaches during 7-day follow-up.
We are not aware of any evidence-based treatment for acute post-traumatic headache or other reports of metoclopramide for this type of headache. In a retrospective description of management of post-traumatic headache in a pediatric ED, 93% of patients reported 50% improvement in pain scores after receiving an anti-dopaminergic [6]. A randomized comparison of metoclopramide with ondansetron for post-traumatic nausea demonstrated modest improvement in both groups [7]. Parenteral metoclopramide is commonly used in the ED setting to treat acute primary headache [8]. It is an evidence based-treatment of both tension-type headache [4] and migraine [3]. It is unclear whether or not diphenhydramine is needed—patients who received 20 mg of metoclopramide report subjective restlessness less frequently if they are co-administered diphenhydramine [9].
One week after the ED visit, a quarter of the cohort reported persistent headaches, though these tended not to be functionally impairing. It is not clear how these patients should be treated. Acute care clinicians should warn their post-traumatic headache patients at the time of discharge that their headache may recur and provide these patients with a contingency plan for how to treat their headaches.
Limitations of this work include an open-label design, which can cause both research participants and research personnel to overestimate medication efficacy. Our small sample size causes imprecision in estimates of outcomes. Our rationale for the small sample size is as follows: this was an exploratory study to determine if metoclopramide was a reasonable treatment for acute post-traumatic headache. Our goal was to enroll just enough patients to obtain an estimate of efficacy that could then be used to plan a randomized trial. We chose twenty patients with available primary outcome data as a reasonable number to accomplish this goal. Finally, we did not use a placebo control in this study. Therefore, despite showing improvement of symptoms, we cannot conclude that this treatment regimen is more effective than placebo. A well-powered, randomized, placebo-controlled study is needed.
In conclusion, IV metoclopramide 20 mg plus diphenhydramine 25 mg is a moderately effective and well-tolerated medication regimen for patients presenting to the ED with acute post-traumatic headache. However, 1/3 of patients report headache relapse after ED discharge and 1/4 of patients report persistent headaches one week later.
Appendix A. Post Concussion Symptom Scale
0 to 6 sale on which 0 = none and 6 = severe
Headache
Pressure in head
Neck Pain
Balance problems
Nausea or vomiting
Blurred vision
Dizziness
Not feeling right
Confusion
Feeling slowed down
Feeling like “in a fog”
Drowsiness
Fatigue or low energy
More emotional than usual
Irritability
Difficulty concentrating
Difficulty remembering
Sadness
Nervous or Anxious
Difficulty falling asleep
Sensitivity to light
Sensitivity to noise
Footnotes
This publication was supported in part by the Harold and Muriel Block Institute for Clinical and Translational Research at Einstein and Montefiore grant support (UL1TR001073).
We have no conflicts of interest to report.
References
- 1.Blyth BJ, Bazarian JJ. Traumatic alterations in consciousness: traumatic brain injury. America]–>Emerg Med Clin North Am. 2010;28(3):571–94. doi: 10.1016/j.emc.2010.03.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Seifert TD, Evans RW. Posttraumatic headache: a review. Curr Pain Headache Rep. 2010;14(4):292–8. doi: 10.1007/s11916-010-0117-7. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1111/head.12835. [DOI] [PubMed] [Google Scholar]
- 4.Friedman BW, Adewunmi V, Campbell C, Solorzano C, Esses D, Bijur PE, et al. A randomized trial of intravenous ketorolac versus intravenous metoclopramide plus diphenhydramine for tension-type and all nonmigraine, noncluster recurrent headaches. Ann Emerg Med. 2013 doi: 10.1016/j.annemergmed.2013.03.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Olesen J, Bendtsen L, Dodick D, Ducros A, Evers S, First M, et al. The International Classification of Headache Disorders, 3rd edition (beta version) Cephalalgia: an international journal of headache. 2013;33(9):629–808. doi: 10.1177/0333102413485658. [DOI] [PubMed] [Google Scholar]
- 6.Chan S, Kurowski B, Byczkowski T, Timm N. Intravenous migraine therapy in children with posttraumatic headache in the ED. J Emerg Med]–>Am J Emerg Med. 2015;33(5):635–9. doi: 10.1016/j.ajem.2015.01.053. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Zamani M, Namdar B, Azizkhani R, Ahmadi O, Esmailian M. Comparing the antiemetic effects of ondansetron and metoclopramide in patients with minor head trauma. Emerg (Tehran) 2015;3(4):137–40. [PMC free article] [PubMed] [Google Scholar]
- 8.Friedman BW, West J, Vinson DR, Minen MT, Restivo A, Gallagher EJ. Current management of migraine in US emergency departments: an analysis of the National Hospital Ambulatory Medical Care Survey. Cephalalgia. 2015;35(4):301–9. doi: 10.1177/0333102414539055. [DOI] [PubMed] [Google Scholar]
- 9.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. Ann Emerg Med. 2009;53(3):379–85. doi: 10.1016/j.annemergmed.2008.08.003. [DOI] [PubMed] [Google Scholar]