Ketamine for Refractory Headache: A Retrospective Analysis

Abstract

Background and objectives:
The burden of chronic headache disorders in the United States is substantial. Some patients are treatment refractory. Ketamine, an N-methyl-D-aspartate antagonist, provides potent analgesia in subanesthetic doses in chronic pain, and limited data suggest it may alleviate headache in some patients.

Methods:
We performed a retrospective study of 61 patients admitted over 3 years for 5 days of intravenous therapy that included continuous ketamine to determine responder rate and patient and ketamine infusion characteristics. Pain ratings at 2 follow-up visits were recorded. An immediate responder was a patient with decrease of 2 points or greater in the numerical rating scale (0-10) from start to final pain in the hospital. Sustained response at office visits 1 and 2 was determined based on maintaining the 2-point improvement at those visits. Patients were assessed daily for pain and adverse events (AEs).

Results:
Forty-eight (77%) of the 61 patients were immediate responders. There were no differences regarding demographics, opioid use, or fibromyalgia between immediate responders and nonresponders. Maximum improvement occurred 4.56 days (mean) into treatment. Sustained response occurred in 40% of patients at visit 1 (mean, 38.1 days) and 39% of patients at visit 2 (mean, 101.3 days). The mean maximum ketamine rate was 65.2 ± 2.8 mg/h (0.76 mg/kg per hour). Ketamine rates did not differ between groups. Adverse events occurred equally in responders and nonresponders and were mild.

Conclusions:
Ketamine was associated with short-term analgesia in many refractory headache patients with tolerable adverse events. A prospective study is warranted to confirm this and elucidate responder characteristics.

Full text

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Ketamine for Refractory Headache
ARetrospectiveAnalysis
Eric S. Schwenk, MD,* Amir C. Dayan, MD,* Ashwin Rangavajjula, MD,†Marc C. Torjman, PhD,*
Mauricio G. Hernandez, BS,* Clinton G. Lauritsen, DO,‡Stephen D. Silberstein, MD,‡
William Young, MD,‡and Eugene R. Viscusi, MD*
Background and Objectives: The burden of chronic headache disor-
ders in the United States is substantial. Some patients are treatment refrac-
tory. Ketamine, an N-methyl-D-aspartate antagonist, provides potent
analgesia in subanesthetic doses in chronic pain, and limited data suggest
it may alleviate headache in some patients.
Methods: We performed a retrospective study of 61 patients admitted
over 3 years for 5 days of intravenous therapy that included continuous ke-
tamine to determine responder rate and patient and ketamine infusion char-
acteristics. Pain ratings at 2 follow-up visits were recorded. An immediate
responder was a patient with decrease of 2 points or greater in the numer-
ical rating scale (0–10) from start to final pain in the hospital. Sustained re-
sponse at office visits 1 and 2 was determined based on maintaining the
2-point improvement at those visits. Patients were assessed daily for pain
and adverse events (AEs).
Results: Forty-eight (77%) of the 61 patients were immediate responders.
There were no differences regarding demographics, opioid use, or fibromy-
algia between immediate responders and nonresponders. Maximum im-
provement occurred 4.56 days (mean) into treatment. Sustained response
occurred in 40% of patients at visit 1 (mean, 38.1 days) and 39% of patients
at visit 2 (mean, 101.3 days). The mean maximum ketamine rate was
65.2 ± 2.8 mg/h (0.76 mg/kg per hour). Ketamine rates did not differ
between groups. Adverse events occurred equally in responders and nonre-
sponders and were mild.
Conclusions: Ketamine was associated with short-term analgesia in many
refractory headache patients with tolerable adverse events. A prospective
study is warranted to confirm this and elucidate responder characteristics.
(RegAnesthPainMed2018;43: 00–00)
Ketamine, a phencyclidine derivative, is a dissociative anes-
thetic that provides potent analgesia at subanesthetic doses.
It is an N-methyl-D-aspartate (NMDA) receptor antagonist, which
is thought to be the primary mechanism responsible for its analge-
sic properties. In addition, ketamine acts on opioid, non-NMDA
glutamatergic, and muscarinic cholinergic receptors; facilitates
γ-aminobutyric acid signaling; and has local anesthetic proper-
ties.
1
Subanesthetic ketamine may also be effective for short-
term relief of chronic migraine and other refractory headache dis-
orders,
2,3
which affect up to 2% of the population of the United
States, inflicting a major clinical and financial burden on patients
and the health care system.
4
The mechanism by which ketamine is
effective in treating headache pain is not entirely clear. However,
memantine,
5,6
magnesium,
7
and amantadine,
8
all NMDA receptor
antagonists, may be effective for headache and migraine prophy-
laxis, which supports the involvement of the NMDA receptor.
N-methyl-D-aspartate receptor antagonism may decrease chronic
pain by inhibiting glutamate-induced neurotoxicity, decreasing
central sensitization and specifically in migraines by inhibiting
cortical spreading depression.
9
Our clinical experience suggests
that there are many patients who experience substantial relief
and a smaller group of others who do not benefit from this therapy.
We therefore performed a retrospective analysis of patients admit-
ted to our hospital for treatment of refractory headaches over a
3-year period to determine responder rate and patient and keta-
mine infusion characteristics.
METHODS
After approval by the institutional review board (Thomas Jef-
ferson University, January 16, 2014, Control #14D.552), we con-
ducted a retrospective chart review of 61 consecutive patients
from January 2014 through December 2016 admitted to Thomas
Jefferson University Hospital for intravenous (IV) treatment of re-
fractory headache with ketamine infusion. All patients with data
available were included. Patients who had previously received ke-
tamine for refractory headache were excluded. Patients were ad-
mitted to the neurology service in conjunction with the Jefferson
Headache Center for aggressive IV therapy, and the acute pain
management service (APMS) was consulted for management of
IV ketamine for each patient. The APMS consists of a physician-
led, nurse-driven team that provides coverage 24 hours per day,
7 days per week, with weekend time being covered by residents.
Acute pain management service nurses are permitted to adjust keta-
mine infusion rates within the context of a protocol, but they do not
From the *Department of Anesthesiology, Sidney Kimmel Medical College at
Thomas Jefferson University; †Department of Anesthesiology, Thomas Jeffer-
son University Hospital; and ‡Department of Neurology, Thomas Jefferson
University, Philadelphia, PA.
Accepted for publication March 25, 2018.
Address correspondence to: Eric S. Schwenk, MD, Department of
Anesthesiology, Sidney Kimmel Medical College at Thomas Jefferson
University, Suite 8130, Gibbon Bldg, 111 South 11th St, Philadelphia, PA
19107 (e‐mail: Eric.Schwenk@jefferson.edu).
E.S.S. has received consulting fees from Avenue Therapeutics. C.G.L. has
received honoraria from Cefaly Technology. S.D.S. receives, or has
received, honoraria from Alder Biopharmaceuticals; Allergan, Inc; Amgen;
Avanir Pharmaceuticals, Inc; Curelator, Inc; Dr Reddy's Laboratories;
eNeura Inc; electroCore Medical, LLC; Lilly USA, LLC; Medscape, LLC;
NINDS; Supernus Pharmaceuticals, Inc; Teva Pharmaceuticals; Theranica;
and Trigemina, Inc. W.Y. has received consulting fees from Allergan; he is
on the advisory board for Amgen, Avanir, Cipla, Alder, Eli Lilly, and
Supernus. He has received research support from Allergan, Amgen,
Autonomic Technologies, Colucis, Cumberland, Dr Reddy's Laboratories,
Eli Lilly, Novartis, PCORI, Scion, Teva, and Zosano. Eugene Viscusi has
served as a consultant for AcelRx, Medicines Company, Mallinkrodt,
Trevena, Cara Pharmaceuticals, Salix, AstraZeneca, and Merck. His
institution has received research grants in the past from AcelRx, Adolor,
Progenics, and Pacira.He has been a paid lecturer for AcelRx,Merck, Salix,
and Mallinkrodt. None of these companies were involved in any aspect of
the development of this manuscript. A.C.D., A.R., M.C.T., and M.G.H.
declare no conflict of interest.
Institutional affiliation of manuscript: Department of Anesthesiology, Sidney
Kimmel Medical College at Thomas JeffersonUniversity, Philadelphia, PA.
Source of funding: Departmental funding.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions
of this article on the journal's Web site (www.rapm.org).
Copyright © 2018 by American Society of Regional Anesthesia and Pain
Medicine
ISSN: 1098-7339
DOI: 10.1097/AAP.0000000000000827
CHRONIC AND INTERVENTIONAL PAIN
BRIEF TECHNICAL REPORT
Regional Anesthesia and Pain Medicine •Volume 43, Number 8, November 2018 1
Copyright © 2018 American Society of Regional Anesthesia and Pain Medicine. Unauthorized reproduction of this article is prohibited.

give bolus doses (Appendix A, Supplemental Digital Content 1,
http://links.lww.com/AAP/A257). Admission and scheduling were
based on bed availability, and patients were not necessarily
experiencing migraine exacerbations on admission. The elec-
tronic medical records, daily APMS notes, and the preadmission
and postadmission clinic notes from the Jefferson Headache
Center were retrieved, and the following data were recorded:
name; medical record number; demographics; home medications;
diagnosis, based on International Classification of Headache
Disorders, Third Edition) criteria
10
; pain level on admission
and daily pain level during and at the end of hospitalization;
ketamine infusion rates and changes during admission; the pres-
ence of adverse events (AEs); and medications given to man-
age AEs. Pain levels from the first 2 office visits after discharge
were recorded.
Ketamine infusions were typically started at 10 mg/h for
most patients with a few exceptions and titrated up in increments
of 5 mg/h every 3 to 4 hours to a soft upper limit of 1 mg/kg of
body weight per hour. Adverse events, including hallucinations,
delirium, blurry vision, nightmares, nausea, and hypertension,
were routinely assessed. These AEs were the primary limiting fac-
tor in the rate and degree of titration. Admissions were planned to
be 5 days unless a patient could not tolerate the full course of treat-
ment or other factors dictated a longer admission. A clonidine
patch was used for management of psychomimetic and sympatho-
mimetic adverse effects. A benzodiazepine was also available
as needed for treatment of AEs. Other medications routinely
ordered by the headache service included, but were not limited to,
prochlorperazine, metoclopramide, methylprednisolone, and ketorolac.
In general, home analgesics were continued. Daily opioids were
being used for management of other comorbid refractory chronic
pain conditions, not for the management of refractory headache.
In general, patients were routinely counseled by the outpatient
headache providers on the risk of opioid use, including medication
overuse headache (MOH). Opioids were being prescribed by
nonheadache providers. Patients were encouraged to minimize
the daily dose of opioids, and attempts were made to coordinate
alternative management of chronic nonheadache pain disorders
with other providers.
We predefined an “immediate responder”as a patient who
experienced a decrease in pain rating of 2 points on a 0- to 10-
point numerical rating scale (NRS) from beginning pain to end
pain, consistent with previous investigations.
2,11
A“sustained re-
sponder”was defined as an immediate responder who maintained
at least a 2-point decrease at the first 2 postdischarge office visits
in the Jefferson Headache Center, each of which was analyzed in-
dependently. These 2 visits are intended to occur at 30 and 90 days
after discharge but because of scheduling reasons can vary by
several weeks.
Continuous parametric data were analyzed using the Student
ttest for independent groups and the χ
2
test or Fisher exact test, as
appropriate, for categorical data. All statistical analyses were per-
formed using SYSTAT version 13 (Systat Software Inc, San Jose,
California), with P< 0.05 set for statistical significance. Data are
reported as mean ± SEM unless otherwise stated. For office visits
1 and 2, percentages of patients with sustained response were
TABLE 1. Demographic Data
Variable All Patients (n = 61)
Male/female, n 44/17
Age, mean (range), y 42.4 (20 –65)
Weight, mean (SEM), kg 85.4 (2.7)
Migraine, n (%) 59 (97)
Cluster headache, n (%) 2 (3)
Variable Immediate Responders (n = 48) Nonresponders (n = 13) P
Male patients, n (%) 13 (27) 6 (46) 0.191
Age, mean (SEM), y 43.2 (1.7) 39.2 (3.4) 0.355
Daily opioid use, n (%) 32 (67) 6 (46) 0.570
Fibromyalgia, n (%) 9 (19) 2 (15) 0.781
TABLE 2. Additional Medications Used for Patients With
Refractory Headache
Immediate Responders
(n = 48)
Nonresponders
(n = 13)
IV/nasal DHE 14 (29.1%) 1 (7.7%)
IV NSAIDs 22 (45.8%) 6 (4.6%)
PO NSAIDs 8 (16.6%) 1 (7.7%)
IV neuroleptics 10 (20.8%) 1 (7.7%)
PO neuroleptics 24 (50%) 8 (61.5%)
IV anticonvulsants 2 (4.2%) 0
PO anticonvulsants 21 (43.8%) 5 (38.4%)
DHE indicates dihydroergotamine; NSAID, nonsteroidal anti-inflammatory
drug; PO, by mouth.
TABLE 3. Adverse Events From Ketamine Infusions
Adverse Events
Immediate Responders
(n = 48)
Nonresponders
(n = 13) P
Nystagmus 36 (75) 7 (54) 0.141
Sedation 23 (48) 8 (62) 0.319
Nausea/vomiting 19 (40) 4 (31) 0.564
Blurry vision 17 (35) 6 (46) 0.482
Hallucinations 13 (27) 4 (31) 0.794
Vivid dreams 5 (10) 3 (23) 0.234
Data are presented as n (%).
Schwenk et al Regional Anesthesia and Pain Medicine •Volume 43, Number 8, November 2018
2© 2018 American Society of Regional Anesthesia and Pain Medicine
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based on patients with available data. Missing patients were not in-
cluded in those analyses.
RESULTS
Headache Pain Outcomes
A total of 61 unique patients were identified and included in
the study. Demographics are shown in Table 1. It is notable that
13 patients (27%) of the immediate responders and 5 patients
(39%) of the nonresponders used daily opioids and met the criteria
for MOH.
12
There was no difference between groups regarding
MOH (P= 0.499). Additional medications administered during
admission included dihydroergotamine, nonsteroidal anti-inflammatory
drugs, neuroleptics, and anticonvulsants (Table 2). Fifty-nine of
the 61 patients had a diagnosis of refractorymigraineonadmission,
and 2 patients had cluster headache. The mean length of infusion
was 5.1 ± 0.1 days. The mean pain rating on admission was
7.5 ± 0.2 out of 10 (NRS); this decreased to 3.4 ± 0.3 at the end
of ketamine therapy (P<0.001).
Using the predetermined definition of immediate responder
as a patient with a decrease in pain rating of 2 out of 10 or greater,
48 (77%) of 61 patients were classified as immediate responders.
There were no differences between immediate responders and
nonresponders with regard to age, sex, history of opioid use, his-
tory of fibromyalgia, and presence of AEs (Tables 1 and 3). The
mean NRS initial pain rating for immediate responders was
7.8 ± 0.23 and 6.8 ± 0.64 for nonresponders. At the end of treat-
ment, the mean pain rating for immediate responders was
2.63 ± 0.28 compared with 6.62 ± 0.68 for nonresponders
(P< 0.01; Fig. 1). The mean time to lowest pain rating was
4.56 days into the admission for immediate responders.
At the first office visit, which occurred 38.1 ± 4.7 days after
hospital discharge, 52 of the original 61 patients had follow-up
data available for analysis. Of the 52 patients, 21 (40%) had
a sustained decrease in pain of 2 points and were classified as
sustained responders. Thirty patients (58%) no longer had sus-
tained response, and 1 patient was not an immediate responder
but did improve at 1 month compared with the end of hospitaliza-
tion. Sustained responders did not differ significantly from nonre-
sponders with regard to age (P=0.437)orsex(P= 0.150). At the
FIGURE 1. Pain experienced during admission by patients withrefractory headaches beingtreated with continuous 5-dayketamine infusions.
FIGURE 2. Percentage of patients characterized as responders acutely and at office visits 1 and 2.
Regional Anesthesia and Pain Medicine •Volume 43, Number 8, November 2018 Ketamine for Refractory Headache
© 2018 American Society of Regional Anesthesia and Pain Medicine 3
Copyright © 2018 American Society of Regional Anesthesia and Pain Medicine. Unauthorized reproduction of this article is prohibited.

second office visit, which occurred 101.3 ± 8.8 days after hospital
discharge, 49 of the original 61 patients had follow-up data avail-
able for analysis. Of these, 19 (39%) were classified as sustained
responders (Fig. 2), whereas 30 (61%) were not sustained re-
sponders at the second office visit. There were no differences be-
tween sustained responders and nonresponders at this second
office visit according to age (P= 0.188) or sex (P=0.979).
Ketamine Infusion Characteristics
The mean starting ketamine infusion rate for all patients
was 11.0 ± 0.6 mg/h (Table 4, Fig. 3). The mean weight was
85.4 ± 2.7 kg. The mean maximum ketamine infusion rate was
65.2 ± 2.8 mg/h, which is 0.76 mg/kg per hour. At the time of
the lowest pain rating, the mean ketamine infusion rate was
54.5 ± 3.5 mg/h. There was no difference in mean ketamine infusion
rate in immediate responders compared with nonresponders over
the entire course of treatment (43.7 ± 4.2 vs 44.1 ± 1.9 mg/h;
P= 0.933). There was also no difference in the mean maximum
ketamine infusion rate between immediate responders and nonre-
sponders (64.8 ± 3.0 vs 66.8 ± 7.2 mg/h; P= 0.794).
Adverse Events
Patients were asked daily about the presence of AEs, includ-
ing central nervous system events (hallucinations, vivid dreams,
blurry vision) and nausea and/or vomiting. Sedation was recorded
based on nursing or physician observations. Results were recorded
as “present”or “absent,”and no severity was recorded. Results are
shown in Table 3 in decreasing order of frequency. All AEs were
considered mild and improved following a decrease in ketamine
infusion rate, with the exception of 1 patient, a 52-year-old woman
who experienced nausea, blurry vision, and sedation on day 2 of
treatment and elected to stop ketamine.
DISCUSSION
Our retrospective study of inpatient ketamine infusion shows
that more than three quarters of patients with refractory headache
were immediate responders, and approximately half maintained
the improvement up to 3 months after the infusion. Although it
cannot be proven that ketaminewas solely responsible for the pain
relief because of the retrospective nature of the study, it is encour-
aging and suggests the need for larger, prospective studies in this
challenging patient population. The US burden of chronic mi-
graine, which comprised 97% of the diagnoses in our cohort, is
substantial, with a prevalence of approximately 1% of the popula-
tion.
13
The subset of this group carrying a refractory migraine di-
agnosis is approximately 5%,
13
and these patients have substantial
disability and poor overall quality of life.
Our results mirror and expand upon other retrospective stud-
ies with positive results using ketamine for immediate relief of re-
fractory headache.
2,3
One prospective, randomized, double-blind
study reported that subcutaneous ketamine improved acute and
subacute pain associated with migraine headaches in 17 patients,
although the dosing strategy was unusual.
14
Our patients achieved maximum pain relief after more
than 4 days into their admission. This suggests that satisfactory
pain relief may not be achieved after 1 day of treatment, and im-
portantly, not achieving the desiredeffect during the first few days
does not mean further improvement will not occur. Although the
mean ketamine infusion rate increased from day 1 to day 4, by
day 3 the mean ketamine rate wasgreater than 80% of the eventual
maximum rate, yet patients continued to experience additional im-
provement in headache pain. Nonresponders experienced mild
improvement by day 2 but no further reduction in headache inten-
sity beyond that. Taken together, this suggests clinicians should be
patient and wait at least 4 or 5 days before determining that some-
one did not respond to ketamine. For most patients, this requires a
full 5-day treatment course.
What patient characteristics might help predict response?
None of the demographic factors or the presence of fibromyalgia
or current opioid use was significantly associated with response to
ketamine. Fibromyalgia and opioid use are potential confounders,
TABLE 4. Ketamine Infusion Data
Immediate
Responders
(n = 48)
Nonresponders
(n = 13) P
Mean starting rate, mg/h 11.0 (0.7) 10.8 (0.8) 0.853
Mean infusion rate, mg/h 43.7 (4.2) 44.1 (1.9) 0.933
Maximum infusion rate, mg/h 64.8 (3.0) 66.8 (7.2) 0.794
Data are presented as mean (SEM).
FIGURE 3. Ketamine infusion rates at various points of treatment.
Schwenk et al Regional Anesthesia and Pain Medicine •Volume 43, Number 8, November 2018
4© 2018 American Society of Regional Anesthesia and Pain Medicine
Copyright © 2018 American Society of Regional Anesthesia and Pain Medicine. Unauthorized reproduction of this article is prohibited.

given the evidence supporting ketamine for short-term relief in fi-
bromyalgia,
15
as well as studies showing opioid-tolerant patients
especially benefit from ketamine.
16,17
Well-designed prospective
studies are needed to better elucidate these characteristics as retrospec-
tive data have limitations. Other factors might help predi ct response
to ketamine, such as individual metabolism of the drug.
18
Metab-
olites of ketamine, including hydroxyketamine, dehydronor-
ketamine, and other hydroxynorketamine molecules, may play a
role in the treatment of depression,
19
and they could also be im-
portant in chronic pain conditions such as complex regional pain
syndrome.
18
There is a subset of migraine and complex regional
pain syndrome patients who have favorable response to ketamine,
whereas others have minimal relief. Tailoring treatment based on
likelihood of response would be useful to patients and clinicians.
This is an area worthy of future study.
The widespread use of ketamine for refractory headache dis-
orders remains challenging. The psychomimetic AEs, including
hallucinations, vivid dreams, and other central nervous system
excitation, associated with ketamine deter many from using it.
In addition, because it is approved as an anesthetic, it requires
monitoring that varies by state and hospital. The incidence of such
undesirable AEs in a review of postoperative patients was approx-
imately 7%.
20
In a mixed medical-surgical population receiving
subanesthetic ketamine infusions, an incidence of 16% was re-
ported, whereas in a refractory headache population this was as
high as 20% of patients with a mean ketamine rate of 0.53 mg/kg
per hour.
2
Our incidence of hallucinations (28%) was higher than
these reported results, and this may have been a result of our fairly
aggressive titration of ketamine with a mean maximum rate of
65 mg/h (0.76 mg/kg per hour). Despite our higher rates, only
1 patient discontinued infusion because of intolerance of AEs.
This is encouraging as higher doses appear to be well tolerated
by most patients.
In addition to the inherent limitations of any retrospective
study, this study has several additional limitations. First, patients
were not necessarily admitted for treatment during an acute exac-
erbation of migraine; thus, initial pain ratings may not have re-
flected the overall state of the headache disorder. Second, our
ketamine protocol does not mandate a specific starting dose and
allows for some clinical judgment in rate increases and decreases.
There is variation in the titration strategy among our individual
APMS physicians. Third, because 97% of patients in the study
had a migraine diagnosis, it is not clear how generalizable these
results would be to patients with other headache diagnoses. Last,
we were unable to retrospectively determine with certainty if pa-
tients had any changes in treatment or other interventions after
hospital discharge that could have affected level of pain at subse-
quent office visits. This limitation likely did not play a major role
in the results as all patients in the study had refractory headaches
and were unlikely to have responded to other minor interventions
during that time.
In conclusion, subanesthetic ketamine infusion was associ-
ated with improved acute pain in a group of patients with refractory
headaches, many of whom continued to experience decreased pain
3 months after treatment. Ketamine is a promising potential ther-
apy for thousands of refractory patients who have not found relief
elsewhere. Ketamine infusion is well tolerated within the context
of our protocol. Prospective studies should focus on responder
characteristics and optimal dosing strategies that minimize AEs
while providing optimal headache relief.
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Regional Anesthesia and Pain Medicine •Volume 43, Number 8, November 2018 Ketamine for Refractory Headache
© 2018 American Society of Regional Anesthesia and Pain Medicine 5
Copyright © 2018 American Society of Regional Anesthesia and Pain Medicine. Unauthorized reproduction of this article is prohibited.