A Randomized Placebo-Controlled Trial of Sub-Dissociative Ketamine for Treatment of Acute Migraine-Type Headache in the Emergency Department
Phase: NA
Conditions: Headache
Sponsor: Carilion Clinic

Low-dose Ketamine Does Not Improve Migraine in the 
Emergency Department: A Randomized Placebo- 
controlled Trial  
 
 
NCT02697071 
 
6/6/2017 
 
Ashley R. Etchison, MD, 
* Lia Bos, MD,
* Meredith Ray, PhD, MPH,
† Kelly B. McAllister, PharmD, MBA,
‡ Moiz 
Mohammed, BS,
‡ Barrett Park, MD,
‡ Allen Vu Phan, MD, 
* and Corey Heitz, MD, MS
§ 
 
*Virginia Tech Carilion School of Medicine, Roanoke, Virginia  
†University of Memphis, Department of Epidemiology, Biostatistics and Environmental Health, Memphis, 
Tennessee  
‡Carilion Roanoke Memorial Hospital, Department of Emergency Medicine, Roanoke, Virginia 
§Lewis Gale 
Medical Center, Department of Emergency Medicine, Salem, Virginia Corresponding author. Address for 
Correspondence: Ashley R. Etchison, MD, Virginia Tech Carilion School of Medicine, 1906 Belleview Ave SE, 
Roanoke, VA 24014, Roanoke, VA. Email: ashleyetchison@gmail.com.  

INTRODUCTION  
Migraine is a debilitating primary headache disorder that affects one in seven adult Americans annually.
1 Many 
headache sufferers visit emergency departments (EDs) to alleviate migraine-associated pulsating head discomfort, nausea, 
vomiting, phonophobia and photophobia. American  
Headache Society guidelines recommend intravenous (IV) prochlorperazine and metoclopramide and 
subcutaneous sumatriptan for eligible adults presenting to the ED with migraine, but these medications are 
associated with adverse events and contraindications.
2 Prochlorperazine and  
metoclopramide can cause akathisia and are administered with diphenhydramine, which treats akathisia but 
sedates patients.
3–4 Dopamine antagonists like metoclopramide may cause dystonic reactions and Parkinsonism.
5 Triptans 
are contraindicated in patients with vascular disease,  
uncontrolled hypertension, and pregnancy; side effects include dizziness, chest pressure, and limb heaviness.
6  
Recently proposed migraine treatments include sedating and anesthetic drugs. For example, propofol was shown to be equally 
effective as sumatriptan for acute migraine in the ED.
7 Like propofol, ketamine is used for anesthesia induction but exhibits a 
different mechanism of action.  
Ketamine, a noncompetitive n-methyl-D-aspartate (NMDA) receptor antagonist, acts as a rapidly dissociative 
amnestic. It is frequently used for procedural sedation at dissociative doses of 1.0 milligrams per kilogram 
(mg/kg) or greater in the ED.
8 At doses less than 1.0 mg/kg ketamine  
exhibits hypoalgesic effects on nociceptive stimuli and alleviates chronic pain, cancer pain, neuropathic pain, 
and peri-operative pain.
9,10 In the ED, low-dose IV ketamine provides analgesia for acute abdominal, flank, and 
musculoskeletal pain that is comparable to morphine.
11,12 A review  
concluded that ketamine doses of 0.3 mg/kg or less are acceptable treatment for acute pain in the ED and 
result in fewer cardiopulmonary adverse events compared to opioid use.
13  
Our primary goal was to compare the efficacy of low-dose IV ketamine vs. saline placebo in the  
treatment of acute migraine using Numeric Rating Scale (NRS)-11 pain scores as our primary outcome.
14 
We posited that low-dose IV ketamine would be superior to placebo in NRS score reduction after 30 minutes.  
METHODS  
Study Design and Setting  
This was a randomized, placebo-controlled, double-blinded trial conducted in the ED at a medical school-
affiliated academic hospital with a Level I trauma center that accommodates over 90,000 visits annually. This 
study was approved by the facility’s institutional review board and registered with clinicaltrials.gov.  
Study Protocol  
A convenience sample of patients was enrolled over 12 months by a team of trained researchers including 
research assistants, physicians, and medical students. Researchers received the International Headache Society 
(IHS) diagnostic criteria for migraine with aura, migraine without aura, and probable migraine with or without 
aura prior to beginning enrollment. These were reviewed with the primary authors of the paper (AE, LM, CH). 
Each researcher was assigned full-time patient recruitment shifts throughout the enrollment year during daytime 
and evening hours on weekdays and weekends. Because some periods of time could not be covered by 
researchers, continuous recruitment coverage during the enrollment year was not feasible. The assigned 
researcher performed real-time chart review of headache patients in the ED waiting room. After confirming with 
the attending emergency physician (EP) that patients had not received treatment in the ED, the researcher 
reviewed inclusion and exclusion criteria with patients. See Figure 1 for complete inclusion and exclusion 
criteria. Patients then provided written informed consent.  

 
Inclusion and exclusion criteria in accordance with the International Headache Society (IHS) Clinical Trials. bpm, beats per 
minute.  
Subcommittee for guidelines for controlled trials in migraine.
15  
 
Population Health Research Capsule  
What do we already know about this issue?  
Low-dose ketamine has been shown to be effective for acute painful conditions in the emergency department 
and other settings.  
What was the research question?  
Is low-dose ketamine effective for migraine headache in an emergency department setting?  
What was the major finding of the study?  
Ketamine, at a dose of 0.2mg/kg, shows no benefit over placebo for migraine headache at 30 minutes.  

How does this improve population health?  
Migraine headache is a common presenting complaint in the United States. Multiple effective treatments 
are available, but ketamine does not seem to be effective at this dose.  
 
Patients were randomized into one of two treatment arms. Pharmacy completed block randomization using a 
random number generator to ensure roughly equal numbers in each group. Patients were assigned a subject 
number that corresponded with a numbered syringe containing an equivalent volume of normal saline or 
ketamine. Study drug preparation was managed by ED pharmacy staff and overseen by an ED pharmacist. Both 
ketamine and placebo were prepared in 30 mL aliquots, placed in identical syringes, and sequentially labeled. 
Syringes were stocked in a refrigerator requiring a key for entry that was stored in a secured Pyxis MedStation in 
the ED. At no point did the primary investigator or researchers participate in study drug preparation and 
stocking. ED providers, nurses, researchers, and patients were blinded to syringe contents. Study numbers and 
group assignments were securely maintained in the hospital pharmacy and readily available in the event of an 
adverse reaction. Researchers were not aware of subject group assignments prior to study conclusion and 
analysis.  
Demographic and baseline headache data were obtained from each patient including NRS-11 scores (0=“no 
pain” and 10=“worst pain imaginable”), categorical pain intensity score from 0 to 3 (0=“no headache” and 
3=“severe headache”), and functional disability score from 0 to 3 (0=“no disruption of daily activities” and 
3=“performance of daily activities is severely impaired”). Baseline side-effects scores were recorded using Side 
Effects Rating Scale for Dissociative Anesthetics (SERSDA) model often used in ketamine studies (Figure 2).
17,18  
 
 
The treating nurse then obtained the numbered syringe corresponding to each subject’s study number. Study drug 
containing 0.2 mg/kg or an equivalent volume of saline was administered by slow IV push over one minute to each 
subject. Completion of IV push was considered time zero (T0). Researchers returned to bedside at 30 (T30) and 60 
(T60) minutes to record NRS scores, categorical pain scores, functional disability, side effects, and adverse events. 
Ramsay sedation scores were assigned to subjects at T30 and T60. Subjects were asked at T30 if they desired rescue  
medication, which the supervising EP then administered at his discretion. At T60 research investigators asked 
patients about treatment satisfaction and whether they wanted the assigned study medication at a future ED 
encounter. Study participation was complete after T60.  
The assigned researcher recorded all data in real time on paper data collection sheets. Data was reviewed for 

completion and entered into a secured electronic database by the lead research investigator who also 
confirmed written consent from all study participants. Data was processed and analyzed by the statistician 
who was independent of data collection.  
Outcomes  
The primary outcome was the between-group difference in NRS score reduction from baseline to 30 minutes. 
Secondary outcomes included functional disability scores, categorical pain scores, pain response (>50% in NRS 
score and reduction of categorical score to 0 or 1), rescue medication  
request after 30 minutes, and patient satisfaction after 60 minutes.
15 SERSDA side effects, incidence of adverse 
events, and desire for study medication at a future ED encounter were also included in secondary outcomes.  
Data Analysis  
It was determined that a sample size of 32 subjects (16 subjects in each arm) was required to detect a 2.0-point 
difference in the primary outcome (NRSbaseline – NRST30) at 0.8 power. According to previous work we assumed a 
standard deviation of 2.0.
11 Although a difference of 1.3 points on the NRS scale is considered clinically significant, 
we chose 2.0 because this difference correlates with a clinically robust outcome and was employed in previous 
migraine studies.
11,14,19 This analysis was planned as part of a larger analysis of both headache recurrence and acute 
headache relief. The initial enrollment goal was 136 patients to achieve adequate power for recurrence. The 
recurrence arm was abandoned early in enrollment due to extremely low follow-up rates.  
 
We assessed the distribution of patient demographics and clinical measures using chi-square tests (or Fisher’s exact 
test conditional on sample size) and two sample t-tests. Wilcoxon rank-sum tests were used if data was not normally 
distributed. To examine our primary and secondary outcomes, differences within and between study arms at baseline 
and T30 were assessed. NRS scores deviated from a normal distribution; therefore, medians, difference in medians, 
and corresponding interquartile ranges are provided. To better examine the direction of change for outcomes 
measured on an ordinal or Likert-like scale (i.e., functional disability and categorical pain scores), the differences 
from baseline to T30 were categorized as “no change” (no difference between scores), “worsened” (the score 
increased), and “improved” (the score decreased) and was assessed using chi-square tests. All analyses were 
performed in R (R Core Team, Vienna, Austria) at the alpha=0.05 level.  
 
RESULTS  
Subject enrollment occurred from March 2016 to March 2017. We assessed 173 patients for eligibility, and 34 
subjects were randomized to one of two treatment groups (CONSORT diagram Figure 3). All 34 enrolled 
subjects and participating researchers were successfully blinded to treatment group allocation. Table 1 lists 
cohort demographics and baseline information. There were no significant differences between treatment groups. 
One patient had chronic daily hallucinations; at the time of enrollment this was discussed with the primary 
investigator (CH) and the decision was made that given her history of mild, chronic, daily hallucinations that 
were not disruptive to her function, risks would be discussed and she would be allowed to consent and enter the 
study.  

Figure 3  
CONSORT flow diagram.  
ED, emergency department; mg/kg, milligrams per kilogram.  

  
 
 
ICHD, International Classification of Headache Disorders; NRS, Numeric Rating Scale; IQR, interquartile range; ED, emergency 
department; SD, standard deviation.  
 
 

Change in NRS pain scores between groups are listed in Table 2. The primary outcome – between-group 
difference in NRS scores from baseline to 30 minutes – favored saline placebo. This difference was neither 
statistically nor clinically significant. NRS score reductions within each treatment are also in Table 2. Within-
group change for ketamine-treated subjects did not yield clinically significant pain score reduction at 30 minutes. 
Placebo-treated subjects experienced statistically and clinically significant NRS score reduction at 30 minutes. 
Categorical pain and functional disability scores are presented in Table 2. Placebo-treated subjects demonstrated 
a slightly greater improvement in categorical pain and functional outcomes scores at T30, but these  
differences were not significant within or between treatment groups. Fatigue, nausea, and generalized 
discomfort were the most frequently experienced side effects at baseline and T30.  
 
 
SERSDA scores for generalized discomfort were greater in the ketamine arm at baseline and T30,  
which reached statistical significance (Wilcoxon rank-sum test, p=0.0247, p=0.008, respectively) and fatigue was 
greater in the ketamine arm at T60 (Wilcoxon rank-sum test, p=0.0216). Otherwise, there were no statistically 
significant differences in side-effect severity at T30 between the ketamine and placebo arms. There were no adverse 
events in this study. Eighty-eight percent (14/16) of ketamine subjects received a Ramsay score of 2 (patient 
cooperative, oriented, and tranquil) at T30. Two ketamine subjects received Ramsay scores of 3 (patient awake and 
only responds to verbal commands) at T30 but both resolved to scores of 2 at T60.  

Table 3 lists additional secondary outcomes. There were no statistically significant differences between 
arms for these secondary outcomes. Rescue medications were not standardized and comprised a variety of 
treatments, which were not included in the data analysis.  
 
 
DISCUSSION  
The difference in NRS pain scores after 30 minutes was neither statistically nor clinically significant between 
ketamine and placebo groups. Therefore, 0.2mg/kg IV ketamine was not effective in treating acute migraine. 
Neither ketamine nor saline placebo induced pain reduction comparable to that of conventional and novel acute 
migraine therapies. Moshtaghion et al. compared IV propofol to sumatriptan for treatment of migraine in the ED, 
and NRS reductions at 30 minutes were greater than twice the reductions in our results.
7 Coppola et al. compared 
the efficacy of metoclopramide and prochlorperazine to saline placebo. Reductions in NRS scores at 30 minutes 
were 4.2, 7.6, and 1.5, respectively.
20 Although our placebo data is comparable to these results, conventional 
treatments produced twice the amount of pain reduction compared to our results.  
 
A placebo response is evident in our results, and similar responses have been reported in headache literature. Harden 
et al. investigated saline, ketorolac, and meperidine for acute headache treatment in the ED. After one hour saline-
treated patients demonstrated a mean NRS score reduction of 2.82, and nearly 55% of saline-treated patients achieved 
clinical pain relief.
21  
 
Migraine pathophysiology remains complex, making this condition difficult to treat. A postulated component of 
migraine pathophysiology, the “wind-up” phenomenon, is an increase in nociceptive neuron excitability secondary to 
repetitive, frequency-dependent stimulation of nociceptive C-fibers. In humans, this equates to an increase in pain 
perception due to repetitive painful stimuli, also known as temporal summation. Coste et al. used a rat-model to 
demonstrate that “wind-up” enables and enhances the ability of trigeminal neurons to process painful stimuli.
22 This 
relationship is a possible underlying mechanism of chronic headache physiology. NMDA receptors are believed to 

play a role in the “wind-up” phenomenon and contribute to primary hyperalgesia, allodynia, and spontaneous pain 
when activated.
23 Therefore, ketamine’s NMDA antagonism is theorized to induce antihyperalgesic effects in 
migraineurs.  
 
At this time there is a lack of studies investigating low-dose IV ketamine as acute migraine treatment in the ED. 
Headache and head pain have been excluded from prospective trials investigating ketamine for acute pain treatment 
in the ED. Our literature search yielded two prospective, randomized controlled trials investigating subcutaneous 
and intranasal ketamine for migraine treatment. Afridi et al. demonstrated that intranasal ketamine was effective at 
shortening the duration of aura in migraineurs, but pain relief was not measured.
24 Nicolodi et al. investigated 
0.08mg/kg subcutaneous ketamine for acute migraine treatment. There was a greater reduction in pain intensity at 
30 and 60 minutes in the ketamine group vs. the placebo group. There were no reports of dissociation from 
surroundings in the ketamine-treated group, but approximately 50% of treated subjects experienced feelings of 
weak insobriety.
25  
 
Only a few retrospective investigations and case studies have examined IV ketamine for treatment of migraine or 
other headache types. Pomeroy et al. conducted a retrospective study of patients with refractory chronic migraine, 
new daily persistent headache, chronic cluster headache, or visual snow. Patients were admitted to inpatient units and 
treated with continuous IV ketamine infusions for an average of 4.8 days. The mean reduction in NRS score from 
admission to discharge was 3.25, which was statistically and clinically significant. The most common adverse events 
included blurred vision (36.4%), confusion (24.7%), and hallucinations (20.8%). One patient developed suicidality 
and the infusion was halted prematurely.
26  
 
Lauritsen et al. drew similar conclusions with a retrospective case series. All six patients with refractory migraine 
achieved sustained pain relief for >8 hours with an average ketamine infusion dose of 0.34mg/kg/hour. Sustained pain 
relief occurred after an average of 44 hours.
27 While these results are promising for refractory migraine, these 
inpatient studies are not applicable to the ED as shorter treatments are desired for acute stabilization.  
 
Analgesic efficacy of continuous albeit shorter IV ketamine infusions is established in the ED setting. Ahern et 
al. conducted a prospective, nonrandomized, nonblinded study in which IV ketamine infusions were 
administered for various acute pain complaints including abdominal, flank, and, joint pain. Patients were given 
15mg IV push ketamine immediately followed by 20mg/hour IV ketamine infusion, which equates to ~0.3 
mg/kg for a 70 kg individual. After infusion, 65% of patients had clinically significant NRS reductions, and 
68% of patients had clinically significant reductions one hour after infusion.
28  
 
These analgesic benefits, however, are often associated with side effects including dizziness, fatigue, nausea, and, 
as in our study, feelings of unreality without hallucinations.
28 In accordance  
with prior literature, our study used an IV push of ketamine. Recently, Motov et al. demonstrated that subjects 
receiving 15-minute infusions experienced significantly lower rates of feelings of unreality while exhibiting no 
difference in analgesic efficacy compared to IV push.
29  
There is a paucity of knowledge concerning ketamine infusions for acute migraine treatment in the ED. A next step 
from our study is to investigate low-dose IV ketamine infusions for migraine treatment. Miller et al. compared 5-
minute 0.3mg/kg IV ketamine infusions to IV morphine infusions for acute pain in the ED. Ketamine patients 
demonstrated a robust NRS score reduction (4.9 points) in the first five minutes after infusion with scores increasing 
from 5 – 20 minutes.
11 These results illuminate IV ketamine’s complicated analgesic pattern for acute pain. This 
complex pharmacologic course could explain why patients in our study did not experience significant pain relief at 30 
minutes. Perhaps if study participants had rated their pain at 5-minute intervals we might have seen significant pain 
reduction at earlier time points.  
 
Our study demonstrates that a one-time bolus of 0.2mg/kg IV ketamine does not induce clinically significant NRS 

pain score reduction in subjects with acute migraine headache. Further investigation is needed to determine if 
increased dosage, different route of administration, or longer treatment duration increases analgesic efficacy.  
LIMITATIONS  
A limitation in our study was the chosen ketamine dose. At the inception of our work, a standardized analgesic dose 
of IV ketamine for acute pain was not established in the literature. The use of low-dose ketamine for acute migraine 
treatment was reported once in the literature, with a subcutaneous dose of 0.08mg/kg producing a significant pain 
reduction.
25 Lee et al. concluded that low-dose IV ketamine (defined as 0.3mg/kg or less) provides effective 
analgesia that is comparable to opioids, but this data was not published at our study’s inception.
11 Doses between 
0.5–1.0 mg/kg can produce neuropsychiatric side effects such as hallucinations and acute psychosis.
30 Beaudoin et al. 
compared two doses of low-dose ketamine (0.15 and 0.3mg/kg) as adjuvant treatment with morphine for acute pain 
in the ED. Both doses reduced pain, but 0.3mg/kg caused more side effects including nausea and tachycardia.
31 
Recent studies using low-dose ketamine for acute pain used doses of either 0.2mg/kg or 0.3mg/kg with minimal side 
effects.
11,12,31,32 Due to the novel use of low-dose ketamine in migraine patients, a lower dose of 0.2mg/kg was chosen 
for our study.  
 
The subjective quality of patient-reported data in pain studies is a limitation. It is nearly impossible in clinical 
emergency medicine research to obtain a cohort exhibiting equal pain tolerance. The placebo-controlled element of 
our study added an additional limitation. When subjects were informed they might experience neuropsychiatric side 
effects, some patients might have expected these side effects despite receiving placebo. For example, one patient at 
baseline and three patients at T30 reported hallucinations. However, all three patients received placebo. This 
demonstrates the reality of the placebo effect, as well as the subjectivity of patient-reported scores.  
 
Another limitation in our study was maintaining strict control over additional medications given before or within 30 
minutes of study drug administration. The aim of the study was to investigate ketamine without adjuvant 
medications. During enrollment, the researcher’s task was to communicate with the treating EP to ensure 
medications were not administered outside the study protocol. However, two subjects, one in the ketamine arm and 
one in the placebo arm, received 4mg ondansetron just prior to or during the 30-minute study period. One subject 
received 10 mg of metoclopramide with their study medication (ketamine). This patient was excluded from the 
analysis. We analyzed the data both with and without the two who received ondansetron, with no significant effects 
on any outcome except fatigue at 60 minutes (higher in the ketamine arm when the patients are included), and the 
final analysis was performed with the patients included.  
An additional limitation was quantification of worsening side effects. While SERSDA is frequently used to monitor 
dissociative anesthetic side effects, many SERSDA side effects are also migraine symptoms. For example, it is 
difficult to extrapolate if increases from baseline nausea scores are secondary to ketamine administration or worsening 
migraine symptoms. Because ketamine side effects and migraine symptoms are similar, it was necessary to obtain 
baseline SERSDA scores. Therefore, SERSDA quantified baseline migraine symptom intensities as well as symptom 
progression throughout the study.  

The final limitations include study location and sample size. This study was conducted at a single institution in a 
small city surrounded by a rural area. Subjects were recruited from one ED with a patient population 
representing demographics specific to the geographic region. Thus, the results of our study may have limited 
generalizability. Our sample size, though small, was the minimum number of subjects needed to determine a 
clinically significant difference in pain reduction between study arms. A two-point NRS reduction has been 
previously used as the primary outcome in other migraine and acute pain studies with similar sample sizes.
11,31 
However, a larger sample size would have allowed us to power for clinically important outcomes such as changes in 
categorical pain and functional disability scores, achieving pain response, and rescue medication request.  
 
CONCLUSION  
A single bolus of 0.2mg/kg IV ketamine did not achieve greater NRS score reduction compared to placebo after 
30 minutes. Despite similar pain reduction compared to placebo-treated subjects, ketamine-treated subjects 
exhibited minimal side effects that appeared endurable. Ketamine-treated subjects did not report serious 
neuropsychiatric adverse events, and both cohorts reported similar rates of treatment satisfaction. While the 
tolerability of ketamine in this neurologically sensitive cohort is promising to establish an efficacious dose and 
route of administration, we found that 0.2 mg/kg IV ketamine was not efficacious in treating migraine.  
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