Cephalalgia 2021 (Mar); 41 (3): 318328 ~ FULL TEXT
Pamela M Rist, Carolyn Bernstein, Matthew Kowalski, Kamila Osypiuk, Julie P Connor, Robert Vining, Cynthia R Long, Eric A Macklin and Peter M Wayne
Division of Preventive Medicine,
Department of Medicine,
Harvard Medical School and Brigham and Women's Hospital,
Boston, MA, USA.
Background: Spinal manipulation may reduce migraine frequency, but effects of multimodal chiropractic care on migraine frequency have not been evaluated.
Methods: We conducted a pilot randomized controlled trial comparing multimodal chiropractic care + enhanced usual care (MCC+) versus enhanced usual care (EUC) alone among adult women with episodic migraine. EUC was comprised of usual medical care and migraine education literature. MCC+ participants received 10 sessions of chiropractic care over 14 weeks. Primary aims evaluated feasibility of recruitment, retention, protocol adherence, and safety. Change in migraine days was a secondary aim.
Results: Of 422 patients screened, 61 were randomized over 20 months. Fifty-seven (93%) completed daily migraine logs during the intervention, 51 (84%) completed final follow-up, and 45 (74%) completed all assessments. Twenty-four of 29 MCC+ participants (83%) attended > 75% of the chiropractic sessions. Ninety-eight non-serious adverse events were reported by 26 participants (43%) with 39 events among 11 EUC participants and 59 events among 15 MCC+ participants. MCC+ participants experienced greater reductions in migraine days (-2.9 days for MCC+ vs. -1.0 days for EUC, difference = -1.9; 95% confidence interval: -3.5, -0.4).
Conclusions: Pre-specified feasibility criteria were not met, but deficits were remediable. Preliminary data support a definitive trial of multimodal chiropractic care + enhanced usual care (MCC+) for migraine.
Trial registration: This study is registered at Clinicaltrials.gov
Keywords: Migraine; chiropractic care; randomized clinical trial.
From the FULL TEXT Article:
Although medications are often used as first-line treatments
for migraine, some patients experience intolerable
side effects and may have increased risk for migraine
chronification. [1, 2] As a result, individuals with migraine
often express interest in holistic or integrative approaches
over medication alone as part of a long-term management
strategy.  Integrative treatment approaches that
address pathophysiologic processes involved in migraine
attacks and/or reduce migraine symptoms have potential
to reduce migraine frequency and severity.
Over 75% of migraine patients report associated
neck pain and many note musculoskeletal complaints
such as neck stiffness, muscle tension, or problems with
jaw function.  Emerging models of migraine pathophysiology
suggest migraine-associated neck pain can
be caused by triggering the trigeminocervical neural
complex. [7, 8] Neck pain itself may also facilitate the
onset of migraine attacks. [9, 10] Treatment options
that address musculoskeletal complaints may represent
viable therapeutic options for individuals with
A recent meta-analysis of clinical trials evaluating
spinal manipulation reported small potential reductions
in migraine frequency and pain intensity. 
However, the studies included in this meta-analysis
did not evaluate multimodal chiropractic care, which
includes spinal manipulation as well as joint mobilization,
soft tissue release techniques, posture correction,
relaxation techniques, education, and stretching. [12, 13] Other studies have suggested that massage
therapy, physiotherapy, relaxation, manual trigger
point therapy, and mindfulness may also be promising
treatment approaches for migraine.  Therefore,
a multimodal chiropractic care approach, differentially
applied based on individual characteristics, may result
in larger reductions in migraine frequency and severity.
However, no clinical trials have evaluated the ability of
multimodal chiropractic care to reduce migraine frequency
The goal of this study was to conduct a pilot randomized
controlled trial (RCT) evaluating multimodal chiropractic care (MCC) + enhanced usual care (EUC) versus
EUC alone for adult women with episodic migraine.
Our primary aims were to assess feasibility of participant
recruitment, retention and adherence to the protocol,
and adverse events. As secondary outcomes, we
explored changes in migraine frequency, severity, duration,
and medication use between treatment groups.
The design of the Integrative Migraine Pain Alleviation
through Chiropractic Therapy (IMPACT) study has
been described in detail previously.  The study
was conducted at the Osher Clinical Center at
Brigham and Womens Hospital (Boston, MA).
Participants were recruited through the Partners
HealthCare system as well as online and newspaper
postings. Inclusion criteria were: Female gender, age
2055 years, diagnosis of episodic migraine with or
without aura, ≥1 year of migraine, and experiencing
413 days with migraine during the run-in period.
Exclusion criteria were: Having received chiropractic
care in the past 3 months, any major systemic illness
or unstable medical or psychiatric condition, history of
stroke, carotid artery dissection, or vertebral artery dissection,
head or neck trauma within the past year, diagnosis
of medication overuse headache, new use of
prophylactic medication for migraine headaches
within the last three months, currently taking prophylactic
migraine medications other than propranolol and
topiramate, failure to complete daily migraine logs
during the run-in period, having received Botox treatment
for migraine in the past 6 months, self-reported
current alcohol or substance abuse, and diagnosis of
Ehler-Danlos syndrome. All participants were screened
by the study neurologist (CB) to confirm their migraine
diagnosis according to ICHD-3 criteria. 
All participants signed a written informed consent
document. This study was approved by the Brigham
and Womens Hospital Institutional Review Board
and was prospectively registered (ClinicalTrials.gov
Our study consisted of a 4-week run-in period, followed
by a 14-week intervention period, and then a
4-week post-intervention period. After a phone
screen, potential participants attended an in-person
screening visit with the study neurologist (CB).
Eligible participants who provided informed consent
then participated in a 4-week run-in period to confirm
eligibility with respect to migraine frequency and compliance
with completing daily migraine logs. After the
run-in period, participants attended another study visit
in which migraine logs were reviewed. Participants who
completed their logs and recorded 413 migraine days
during run-in completed additional baseline assessments
and were randomized. Randomization was stratified
by use of prophylactic migraine medication (no
prophylactic medication use or prophylactic medication
use) and by migraine frequency during the run-in
period (47 migraines/month or 813 migraines/
month). Randomization was performed using a computer
generated random permuted block scheme with
random block sizes and 1:1 allocation to multimodal
chiropractic care intervention+EUC or EUC alone
within each stratum. A study investigator (PMR) generated
the allocation scheme and a study research assistant
assigned the participant to the intervention. Study
participants, research assistants, and chiropractors
administering the intervention were not blinded to
treatment assignment. Since this pilot study was not
designed to test for efficacy, our goal was to randomize
60 participants to allow us to obtain estimates of
recruitment and retention rates in preparation for a
fully powered trial. 
Throughout the study, participants completed daily
migraine logs assessing migraine attacks including
severity and duration of attacks and medication use. At
randomization and the end of the intervention and
post-intervention periods, participants completed questionnaires
assessing migraine-related disability, healthrelated
quality of life and psychosocial well-being.
EUC was comprised of usual medical care as prescribed
by the participants physicians as well as
migraine education literature, which included information
published by the American Headache Society on
migraine pathophysiology, symptoms, and triggers,
treatment approaches, and associations between
migraine and sleep, sex, and cardiovascular disease.  Individuals in the EUC group received biweekly
phone calls from the study research assistant
to minimize between-group differences in contact
with the study team. EUC participants were also
given the option of 10 courtesy chiropractic sessions
following completion of the study to enhance recruitment
and retention. Individuals assigned to chiropractic
care+EUC received up to 10 sessions of
chiropractic care over a 14-week period at the Osher
Clinical Center by one of two chiropractors. The chiropractic
care protocol has been described in detail previously.  Briefly, the first chiropractic care visit
included a physical examination assessing cervicothoracic
spine posture, ranges of motion, presence of
myofascial trigger points, cervical and temporomandibular
joint movement restrictions with a focus on
myofascial contributions to cranial-facial pain, tenderness,
hypersensitivity, muscle hypertonicity, and general
muscular imbalances. Results of this examination
were used to classify participants into diagnostic categories,
each of which had pre-specified treatment
approaches (Supplemental Table 1). The protocol was
not rigidly standardized and instead could be customized
to the patients clinical needs and preferences.
Participants could opt out of any component of care,
including spinal manipulation. All treatments applied
in this study were within the scope of chiropractic practice
in the Commonwealth of Massachusetts and
included: posture correction and spinal stabilization
exercises, soft tissue relaxation/release techniques,
spinal manipulation and joint mobilization, relaxation
techniques, education, stretches, and ergonomic modifications.
Treatments provided were recorded in the
participants medical record. After the end of the 14-
week intervention phase, participants completed a 4-
week post-intervention phase in which they did not
receive chiropractic treatments or phone calls and
only completed daily migraine logs.
In this pilot study, our primary outcomes evaluated
feasibility of participant recruitment, retention and
adherence to the protocol, and assessment of adverse
events. Specifically, we aimed to demonstrate that 60
patients could be successfully recruited within 12
months, more than 85% would complete baseline and
outcome assessments, and more than 85% of those in
the chiropractic care+EUC group would attend 75%
of the chiropractic care visits. We also hypothesized
that there would be few and only minor adverse
events reported related to the intervention. As part of
our secondary aims, we also assessed changes in
number of migraine days (our main clinical outcome ), migraine severity (1 to 10 scale), migraine duration
(< 4 hours, 412 hours, or 1324 hours), and
number of acute migraine medications used. Means
of these outcomes were calculated for the run-in
period (baseline), weeks 1114 of the intervention
period (initial follow-up) and during the 4-week
post-intervention phase (final follow-up) to use in
the analysis. We also calculated the responder rate,
defined as participants who had a ≥50% reduction
in days with migraine from the run-in period to either
the initial follow-up or final follow-up.  Additional
secondary outcomes included the evaluation of
Migraine Disability Assessment (MIDAS) [36, 36],
Headache Impact Test (HIT-6) , and
Migraine-Specific Quality of Life [40, 41] domains.
All participants were given instructions at the start
of the study to report any adverse event (AE) to study
staff within 24 hours. Examples of AEs included acute
events (e.g. a fall), chronic issues that worsen (e.g.
chronic pain), side effects of treatment received (e.g.
soreness), any painful or uncomfortable events that
took place during or related to study visits, or any
other changes that participants noticed about their
health and/or safety during the study. Study staff also
called participants in the chiropractic care+EUC
group once a month and participants in the EUC
alone group every 2 weeks to inquire about the occurrence
Statistical methods and analysis
Using the number of participants in a given treatment
group as our denominator, we calculated the
treatment-specific frequency of completion of outcome
assessments. For each participant in the chiropractic
care+EUC group, we calculated the proportion of
attended treatment visits and determined the percentage
of individuals who completed at least 75% of them.
We tabulated AEs for each treatment group by organ
system and classified each AE with its degree of
relatedness to the intervention (unrelated, possibly
We estimated the effect of treatment assignment on
number of migraine days in each outcome assessment
(run-in, initial follow-up, final follow-up) using a linear
mixed-effects model imposing a shared baseline
assumption and assuming an unstructured covariance
structure.  All models were performed using an
intention-to-treat analysis and adjusted for age at randomization
(centered at mean age) and strata.
Estimates are reported as adjusted means and adjusted
difference in means with 95% confidence intervals for
the changes from run-in to both follow-up periods.
An equivalent model and analytic approach were
used for our other secondary outcomes. We also estimated
effects on our primary clinical outcome
by number of migraine days during run-in (47
versus 813 migraine days).
For our primary clinical outcome of migraine days,
we calculated the proportion of participants experiencing
a ≥50% reduction in the number of migraine days
between baseline and the initial or final follow-up and
estimated effects with logistic regression adjusting for
Analyses were conducted using SAS (version 9.4;
SAS institute Inc., Cary, NC).
The study flow is described in Figure 1. Of the 422 individuals
who completed the phone screen, 84 provided
consent and entered the 4-week run-in period. Seventy
individuals attended the final screening visit and 61 were
randomized (29 to chiropractic care+EUC and 32 to
EUC alone). The recruitment period lasted 20 months
(13 July 2017 through 28 March 2019).
Mean age of the women included in this study was
36.4 years (range: 2155 years) and mean migraine frequency
during run-in was 7.6 migraine days (standard
deviation (SD) = 2.2). Six women were taking prophylactic
medications. Baseline characteristics were similar
between the two treatment groups (Table 1).
Of the 61 participants randomized, 59 (97%)
attended the 14-week follow-up visit, and 51 (84%)
returned the 18-week follow-up questionnaires. Fifty-seven
participants (93%) completed the 14-week
migraine logs (26 in the chiropractic care+EUC
group and 31 in the EUC only group), and 51 (84%)
completed the 18-week migraine logs (22 in the chiropractic
care+EUC group and 29 in the EUC only
group) (Figure 1). Forty-five participants (74%) completed
all baseline and outcome assessments.
Each participant in the chiropractic care+EUC
group was eligible to receive 10 sessions for a total of
290 possible sessions, of which 264 were attended
(91%). Of the 29 individuals in the chiropractic
care+EUC group, 24 individuals (83%) attended at
least 75% of the chiropractic sessions. Additional
information about the frequency of treatment modalities
used across all visits is provided in Supplemental
No serious AEs were reported. We observed 98 nonserious
AEs (39 events among 11 participants in the
EUC group and 59 events among 15 participants in
the chiropractic care+EUC group). In the chiropractic
care+EUC group, 15 events among four participants
were possibly related to the intervention and five events
among five participants were related to the intervention.
These events usually involved musculoskeletal
stiffness or migraine. No possibly related or related
AEs were reported in the EUC alone group. Table 2
summarizes the overall number of AEs and the most
common types of AEs according to their MedDRA
system organ class and preferred term. The percentages
of individuals reporting the various types of AEs was
similar across the two treatment groups, with the
exception that those in the chiropractic care+EUC
group were more likely to report musculoskeletal stiffness
(21% of participants) compared to those in the
EUC alone group (6% of participants).
Our regression model estimated the change within
and between treatment groups at both follow-up periods
(Table 3). Those in the chiropractic care+EUC
group experienced a greater change in number of
days with migraine from run-in to the initial followup
(weeks 1114) (mean change = 2.90, 95% CI:
4.04, 1.76) compared to those in the EUC alone
group (mean change = 0.98; 95% CI: 2.03, 0.06)
(between-group difference in mean change = 1.92;
95% CI: 3.46, 0.37). This effect persisted at final
follow-up. Compared to EUC alone, chiropractic
care+EUC resulted in greater reductions in migraine
severity (between group difference in mean change-
= 0.85; 95% CI: 1.77, 0.06), number of acute medications
used (between-group difference in mean
change = 1.36; 95% CI: 3.48, 0.76), and migraine
duration (between group difference in mean change-
= 1.48; 95% CI: 3.44, 0.48) from baseline to initial
follow-up. Effects were slightly attenuated at final
follow-up with the exception of migraine duration,
where there was no effect of chiropractic care+EUC
compared to EUC alone.
For our additional secondary outcomes, those in the
chiropractic care+EUC group had larger decreases in
their scores on the MIDAS from run-in to week 14
(between-group difference in mean change = 5.58
(95% CI: 10.44, 0.72)) and HIT-6 (between group
difference in mean change = 3.62 (95% CI: 6.52,
0.73)) than those in the EUC alone group (Table 3).
Patients in the chiropractic care+EUC group also
experienced larger improvements in MQSL scores from
run-in to week 14 than those in the EUC alone group
although the magnitude of the between-group differences
was small (Table 3).
For our primary clinical outcome of migraine days,
we observed slightly larger effects of chiropractic
care+EUC compared to EUC alone among those
reporting four to seven migraine days during run-in
(between group difference in change = 2.04 (95%
CI: 4.24, 0.14)) than among those reporting eight to
13 migraine days during run-in (between group difference
in change = 1.78 (95% CI: 4.04, 0.47)).
At the initial follow-up, 10 women in the chiropractic
care+EUC group and seven women in the EUC
alone group were considered responders. Chiropractic
care+EUC was associated with a twofold increase in
the odds of being a responder, although confidence
intervals were wide (OR = 2.17, 95% CI: 0.68, 6.95).
Similar results were seen at the final follow-up (11 responders
in the chiropractic care+EUC group and
eight responders in the EUC alone group; OR = 2.59,
95% CI: 0.80, 8.36).
In this pilot study, pre-specific feasibility criteria were
not met, but the deficits were remediable. Recruitment
was slower than planned. The most common recruitment
sources were self-referrals of individuals who
learned about the study from a searchable database
of ongoing studies within the Partners HealthCare
system and referrals from the study neurologist. This
suggests that future trials can enhance recruitment by
additional advertising of the study and by partnering
with additional healthcare providers. Most loss to
follow-up occurred during the final follow-up period
after the end of the intervention. Compliance with
completion of migraine logs, the presumptive primary
outcome of a future trial, was 94% at initial follow-up
and 84% at final follow-up, although only 74% of participants
completed all outcome assessments. Future
trials could enhance retention and compliance with
data collection by focusing outcome assessment to
fewer questionnaires and using electronic data collection
methods that alert participants if they skip questions.
Compliance with treatment was slightly lower
than expected (83% of those in the chiropractic
care+EUC group attended at least 75% of the chiropractic
visits versus our goal of 85%). Future trials in
this population could enhance treatment compliance by
increasing the numbers and locations of providers,
which would increase the ease of scheduling
For our primary clinical outcome of change in migraine days, we observed a mean decrease of ~3 migraine days per month for those randomized to the multimodal chiropractic care (MCC+) + enhanced usual care (EUC) compared to a mean decrease of ~1 migraine day per month for those randomized to EUC alone. This difference in mean change between the two groups may be clinically meaningful since it is comparable to the effect size seen for topiramate,
propranolol, or erenumab compared to placebo, which is a decrease of about 2 days per month.  However, larger-scale studies are needed to determine the efficacy of chiropractic care for migraine. We observed some evidence of clinically meaningful
changes in HIT-6 scores, MSQL role function-restriction,
and potentially MIDAS scores for those randomized to chiropractic care+EUC.  However, effects of chiropractic care+EUC on migraine severity, migraine duration, number of medications used, and MQSL role function preventive and emotional function were not clinically meaningful. 
Some evidence suggests that spinal manipulation
may result in modest reductions in migraine frequency
and pain intensity; however, most studies are small and
have significant methodological limitations.  In this
pilot, we addressed methodologic limitations of some
prior studies by describing and using a rigorous randomization
approach, reporting on compliance and
attrition, and specifying primary clinical outcomes.
Although we did not use a sham control like some
prior studies, we did provide participants in the comparison
group with educational materials and contacted
them bi-weekly to lessen between-group
differences in personal contact with the study team.
An important limitation to prior studies is that they
only evaluated one component of chiropractic care
spinal manipulation.  In clinical practice in the
US, chiropractic care is typically delivered in a multimodal
manner and we hypothesized that this multimodal
approach may result in larger beneficial effects
than spinal manipulation alone. Our preliminary findings
support the promise of this approach.
Chiropractic evaluation sought to identify one or
more of three diagnostic classifications: myofascial
pain syndrome; postural or mechanical spinal disorders;
and temporomandibular dysfunction. Treatment
was individually tailored to address major elements of
the diagnostic categories. The chiropractic care
protocol used in the study was validated by a diverse
team of chiropractic experts using a Delphi method  to ensure that it was evidence-based and representative
of clinical management within the scope of chiropractic
practice across the US. The protocol targeted
diagnosis and treatment of musculoskeletal symptoms
and sequelae, but was flexible enough to account for
variability in presentation and patient preferences. 
Another important aspect of this study was monitoring
of AEs in both the EUC alone and chiropractic
care+EUC groups. Reporting and monitoring of AEs
in non-pharmacological intervention studies is often
inconsistent but is essential to understanding the riskbenefit
balance of these interventions. In this study,
participants were instructed to contact study staff if
they experienced any AEs. In addition, during phone
calls, participants in both groups were asked openended
questions about change in symptoms as well as
directed questions about the presence of symptoms
listed on the informed consent form. All reported
AEs were non-serious and usually involved musculoskeletal
stiffness or changes in migraine symptoms (i.e.
nausea). Prior literature suggests that the type and
number of AEs (e.g. local soreness) observed in this
study are consistent with other trials using similar
treatments and with what is currently known about
manual therapies, postural correction exercises,
stretching, and home exercise treatments. 
These results are similar to a prior study on spinal
manipulation among migraineurs.  However, overall
sample sizes of both this and our study are small and
may not have sufficient numbers to detect rare AEs.
For example, some studies have reported associations
between chiropractic care and cervical artery dissection,
a rare but serious event.  However, the causal nature of this relationship has not been established and is questioned by other studies, which have
reported associations between cervical artery dissection
and primary care practitioner visits  and biomechanical
studies which demonstrated that cervical
manipulation causes significantly less arterial strain
than normal range of motion.  Regardless, all
participants were informed of potential AEs including
cervical artery dissection during the informed consent
process and during discussions with the chiropractor
on types of cervical manipulation. 
Although this study has strengths, including evaluation
of an expert-validated multimodal chiropractic care
protocol, rigorous assessment of AEs, use of migraine
logs to assess outcomes, and randomized treatment
assignment, some important limitations should be
noted. Since this was a pilot study, we were unable to
test for efficacy and estimates of AEs are preliminary.
Also, we were unable to blind participants to their treatment
assignment, which is a typical limitation in trials of
manual therapy. This lack of blinding may have resulted
in more patients in the chiropractic care+EUC group
reporting larger benefits of treatment than those in the
EUC group. Participants in the EUC group also
received less patient contact than those in the chiropractic
care+EUC group and it is plausible that some differences
in clinical outcome measures could be driven by
differences in patient contact.
Although results from this study suggest chiropractic
care may serve a role in migraine management, several
unanswered questions remain. Given the proposed
links between migraine and neck pain, future studies
should explore interactions between chiropractic care,
neck pain, and migraine days. Future research should
also explore different doses of chiropractic care (i.e.
additional treatments or different treatment frequency)
given recent observations of an inverse linear relationship
between spinal manipulation treatments and cerviogenic
headache days.  These studies would inform the design of a large-scale efficacy trial of multimodal chiropractic care for migraine.
Spinal manipulation may reduce migraine frequency, but effects of multimodal chiropractic care on migraine frequency has not been evaluated.
We conducted a pilot randomized controlled trial comparing multimodal chiropractic care plus enhanced usual care versus enhanced usual care alone among adult women with episodic migraine.
Pre-specified feasibility criteria were not met, but deficits were remediable. Preliminary data support a definitive trial of multimodal chiropractic care for migraine.
Declaration of conflicting interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article:
PMR reports no conflicts of interest to disclose.
CB has served as a consultant for Amgen and Percept.
MK has received Board of Directors fees from NCMIC, Inc. and sits on the advisory board of the NCMIC Foundation.
KO, JPC, RV and CRL report no conflicts of interest to disclose.
EAM served as a DSMB member for Novartis Pharmaceuticals and Shire Human Genetic Therapies, served on an advisory committee for Biogen, consulted for Cerevance, Intrance, Inventram, Lavin Consulting, and Myolex, and his institution received grants on his behalf from Amylyx Pharmaceuticals, GlaxoSmithKline, and
Mitsubishi Tanabe Pharmaceuticals.
PMW has received funding from the NCMIC Foundation.
The authors disclosed receipt of the following financial support
for the research, authorship, and/or publication of this
article: This study was made possible by a grant from the
Osher Center for Integrative Medicine; the NCMIC
foundation; Inter-Institutional Network for Chiropractic
Research (IINCR) through Palmer College Foundation; the
Crimson Lion Foundation, Jeannie and Jonathan S Lavine,
Trustees; and National Institutes of Health grants
K24AT009282 and K01HL128791.
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