Headache Medicine 2020, 11(4):85-89 ISSN 2178-7468, e-ISSN 2763-6178
DOI: 10.48208/HeadacheMed.2020.25
Headache Medicine
© Copyright 2020
Central sensitization in episodic and chronic migraine
Marco Antonio Nihi¹ , Paulo Sergio Faro Santos¹, Daniel Benzecry Almeid
Neurological Institute of Curitiba, Neurology - Curitiba, PR - Brazil
Neurological Institute of Curitiba, Neurosurgery - Curitiba - PR - Brazil
In chronic migraine, central sensitization (CS) may play a signicant pathophysiological role, since
it amplies pain signals, causing increased pain and disability. However, there are no studies
conrming CS in other migraine subtypes, such as episodic migraine. The authors studied the
relationship between central sensitization syndrome (CSS) in episodic and chronic migraine and
its severity levels.
To evaluate the occurrence and severity of CS in patients with episodic and chronic migraine,
comparing with a control group.
Central Sensitization Inventory was investigated in adult patients with one of three categories: 1)
episodic migraine, 2) chronic migraine and 3) control group. Group 1 included 35 patients while
groups 2 and 3 comprised 30 subjects.
The study included 63 women (66%) and 32 men (34%). Average age was 34.7 years. Mean
score in the CS Inventory was signicantly different according to groups (episodic migraine 37.3,
chronic migraine 47.0 and control group 20.2). Chronic migraine presented the higher score of
severity, followed by episodic and control group.
Central sensitization is found in episodic migraine patients, although the severity is not as high as in
chronic migraine patients. This evidence may save effort and costs in unnecessary complementary
exams, allowing earlier treatment and better patient satisfaction.
Marco Antonio Nihi
Edited by
Mario Fernando Prieto Peres
Central sensitization syndrome
Central sensitization inventory
Episodic migraine
Chronic migraine
Received: November 14, 2020
Accepted: November 30, 2020
Nihi MA, Santos PSF, Almeida DB
Central sensitization in episodic and chronic migraine
ain is an “unpleasant sensory and emotional experience
associated with, or resembling that associated with, actual
or potential tissue damage".
This experience would prevent
increase in tissue damage through a sensitive alert for own
protection. Peripheral and central sensitization (CS) may occur
after prolonged, repeated or intense nociceptive stimuli.
mechanism works by amplifying the nociceptive response, as
well as decreasing its suppressive signals, resulting in an ac-
tivation of pain pathways after decreased threshold stimuli.
It is assumed that probably the function of sensitization is to
avoid further injury of the affected area and adjacent tissue.
Pathophysiological mechanisms of CS involve changes in
ascending and descending pain pathways, including var-
ious neuromodulators, such as bradykinin and substance
P. In addition, there is presynaptic overproduction of other
factors associated with nociceptive C bers, like: aspartate,
glutamate and nerve growth factor (NGF), which contribute
to neuronal hyperexcitability stimulating second-order post-
synaptic receptors that extends and favors the transmission
of nociceptive stimuli. Some receptors, such as neurokinin
(NK) and N-methyl-D-aspartate (NMDA), when activated,
may cause signicant functional changes, further amplifying
neuronal hyperexcitability and stimulation increase. These
impulses reach other areas, such as the trigeminal-autonomic
tracts, limbic system, thalamus and hypothalamus, supporting
neuronal hyperecitability.
In CS there is also a decrease in
activity of descending pain suppression pathways, evidenced
by the reduction of neurotransmitters such as serotonin, en-
kephalins and gamma-aminobutyric acid (GABA) in the
cortico-reticular system,
locus coeruleus
and hypothalamus.
Central sensitization syndrome (CSS) is a well-described and
recognized phenomenon described in the literature that can
be related to several disorders. Such syndrome may occur
either in pathophysiological processes that holds nociceptive
stimulation for prolonged periods (such as osteoarthritis),
as well as in diseases where tissue damage is not well rec-
ognized (such as bromyalgia).
Other examples include
migraine, temporomandibular disorder, chronic fatigue syn-
drome, restless legs syndrome, primary dysmenorrhea and
irritable bowel syndrome.
In clinical practice, there are few validated tools to help
health professionals to identify signs and symptoms that may
be linked to CSS. The Central Sensitization Inventory (CSI)
is a patient self-report questionnaire which aims to identify
the presence of the main clinical and emotional symptoms
and comorbidities associated with CS and CSS, as well as
numerically quantifying the degree of such symptoms.
purpose of collecting these data is to assist health professionals
in the recognition of sensitization and its severity, for a better
planning treatment, avoiding unnecessary interventions and
Migraine is a primary headache that can be related to severe
disability and is the third most common cause of economic
burden worldwide. It is an inherited disorder of the brain that
involves dysfunction of subcortical structures that modulate sen-
sory input.
Great progress has been made in understanding
the pathophysiology of migraine. However, some questions still
remain about the origin of pain attacks and its chronication.
Despite that the presence of CS is well-described in chronic
migraine, there are no major studies showing the occurrence
of CS in episodic migraine, which would lead to different
forms of treatment. This study analyzes the prevalence of CS
in patients with episodic and chronic migraine, comparing
with a control group.
The study included patients of both sexes, older than 15 years
old. Group 1 included patients with an established diagnosis
of episodic migraine (with or without aura). Group 2 included
patients with chronic migraine. Group 3 (control group) en-
closed patients with no previous history of migraine or other
headaches, as well as any diagnosis of diseases illustrated in
Brazilian Population-CSI (BP-CSI; gure 1.1 and 1.2) Part B.
The diagnosis of episodic and chronic migraine was based on
the 3rd edition of the International Classication of Headache
Disorders (2018). Patients with a documented diagnosis of
any disease listed in BP-CSI Part B were excluded from the
control group. Additionally, pregnant and patients with major
psychiatric disorders were also excluded.
Patient data were obtained through the application of the BP-
CSI in individuals lling one of three categories: control group,
episodic migraine and chronic migraine. This questionnaire
consists of 25 general questions scoring 0 to 100 in order
to identify the presence of CSS symptoms. Higher scores
were related to increased CS phenomena. Each question
was related to one symptom and should be answered as:
0 - Never; 1 - Rarely; 2 - Sometimes; 3 - Often; 4 - Always.
The second part contains ten CSS comorbid diagnoses where
patient should answer Yes or No for each diagnosis as well
as providing for how long it’s been known.
Nihi MA, Santos PSF, Almeida DB
Central sensitization in episodic and chronic migraine
All individuals were recruited in a neurological center basis
from November 2019 to February 2020 and all participants
signed a consent inform. The project was sent and approved
by the Ethics and Research Committee in October 2019.
This was an exploratory, quantitative, observational and
cross-sectional study, based on data from the BP-CSI. Statistical
analysis was performed using SPSS software and ANOVA
one way test. When testing differences by contrasting be-
tween the groups, Games-Howell post hoc analysis was
done. It was considered a p value <0.05 to achieve statistical
Ninety-ve patients took part in this study, from October 2019
to February 2020. The Table 1 summarize the results. 66%
were female (n = 63) and 34% male (n = 32). There was a
higher prevalence of men in the control group (33.3% woman;
66.7% men) versus those with migraine: episodic migraine
(77.1% women; 22.9% men) and chronic migraine (86.7%
women; 13.3% men).
Tabl e 1. Summarized data of patients with episodic (EM) and chronic mi-
graine (CM) and control group (CG). Results are presented as percentage,
and absolute values are found in the text.
Variables Parameters (n=95)
EM 77.1%
CM 86.1%
CG 33..3%
EM 22.9%
CM 13.3%
CG 66.7%
Age group
15-30 46%
30-50 41%
50-70 12%
>70 1%
High school
EM 22.9%
CM 16.7%
CG 3.3%
University education
EM 77.1%
CM 83.3%
CG 96.7%
Figure 1.2. Central sensitization inventory (CSI) - page 2Figure 1.1. Central sensitization inventory (CSI) - page 1
Nihi MA, Santos PSF, Almeida DB
Central sensitization in episodic and chronic migraine
The mean age was 34.7 years (standard deviation: 12.9
years), minimum age of 15 years and maximum of 73. In
subgroups, the average age was 37.8 in episodic migraine,
35.5 in chronic migraine and 36.7 in control group.
Our group had a higher level of education in all subgroups,
where in overall, 15% of them (n = 14) nished only high
school and 85% had university education. In subgroups, this
rate was: control (3.3% high school; 96.7% university educa-
tion), episodic migraine (22.9% high school; 77.1% university
education) and chronic migraine (16.7% high school; 83.3%
university education).
Our study found that the control group had the lowest index in
BP-CSI Part A questionnaire: 20.2 (standard deviation: 8.0).
Episodic migraine had an average of 37.3 (standard devia-
tion: 12.41), and the highest score was found in the chronic
migraine group, with an average of 47.0 (standard deviation:
14.02) The difference in scores between the three groups
was statistically signicant in all comparisons (F=39.783; p
<0.05). The distribution is shown in Figure 2.
Figure 2. BP-CSI (Part A) mean scores in each subgroup.
The analysis of BP-CSI Part A in each subgroup showed
that the chronic migraine group had a higher index when
compared with the episodic migraine and control group (p
<0.05), as shown in Table 2.
Tabl e 2. BP-CSI (Part A) averages compared between each subgroup.
Groups Means Differences Signicance
EM vs. CG
1 7.0 p < 0.001
CM vs. CG
26.8 p < 0.001
CM vs. EM
9.8 p < 0.05
The evaluation of BP-CSI Parts A and B depicted that the
chronic migraine group had the higher number of patients
with severe or extreme levels of CS, followed by the episodic
migraine and control group, respectively (Table 3).
Tabl e 3. Central sensitization levels between each subgroup.
Groups Subclinical Mild Moderate Severe Extreme Total
29 1 - - - 30
10 12 9 2 2 35
3 5 11 5 6 30
The purpose of this study was to evaluate the CS levels in
patients with episodic and chronic migraine, comparing them
with a control group using the BP-CSI. This questionnaire is
useful as a screening tool for CS diagnosis with a cut-off
greater than 40 (total of 100 points; sensitivity of 81% and
specicity of 75%).
Also, this inventory divides patients into
5 categories according to the score obtained: subclinical
(0-29), mild (30-39), moderate (40-49), severe (50-59) and
extreme (60-100), aiding the pain physician as an objective
measurement for future chronic pain studies, control of re-
sponse to treatment, avoiding misdiagnosis and unnecessary
The sample of our patients with migraine was similar to those
described in literature, with two thirds of the patients with
migraine being female (66%).
In our group, 87% of patients
started migraine symptoms in young adulthood.
In the present study, the vast majority of migraine patients
had already completed university education (80%), most-
ly explained by the fact that patients were evaluated in a
private hospital, with a sample of a high socioeconomic
level. North American studies found an inverse relationship
between prevalence of migraine and socioeconomic status,
measured by nancial income or educational level.
such as stressful lifestyle and poor diet can contribute to a
higher incidence in the poorer population. Despite the fact
that socioeconomically deprived individuals have a higher
incidence of migraine and chronication, our evaluation with
individuals with higher education level allowed us to have a
more reliable result in the BP-CSI.
The pathophysiology of chronic migraine suggests the occur-
rence of structural and functional brain changes, including
central sensitization.
In a brain MRI study comparing 11 patients with chronic
migraine and 16 with episodic migraine, structural changes
were identied with a signicant volume decrease in several
areas of the gray matter such as: anterior cingulate gyrus,
amygdala, parietal operculum, inferior frontal gyrus and
insular lobe. In addition, there was a reduction in the ante-
rior cingular cortex and the frequency of migraine attacks.
Nihi MA, Santos PSF, Almeida DB
Central sensitization in episodic and chronic migraine
Increased brain iron deposits have also been detected in
migraine patients. Through high-resolution MRI, Welch et al.
compared patients with episodic migraine (n = 17), chronic
daily headache (CDH; n = 17) and a control group (n = 17).
Increased iron deposition was shown in patients with episodic
migraine and CDH when compared to the control group and
this iron accumulation was positively correlated with disease
duration and migraine chronication.
Functional changes, such as cortical excitability in certain
brain areas, are associated with chronic migraine. Aurora
et al. compared 25 patients with chronic migraine and epi-
sodic migraine patients with a control group. The individuals
underwent PET-CT and there was an increase in metabolism
in the pons and right temporal cortex, suggesting greater
cortical excitability. The researchers concluded that the high
cortical excitability can make patients with chronic migraine
more susceptible to the triggers of the disease, explaining the
high frequency of attacks.
CS is a well-established clinical phenomenon and its con-
cepts have been recognized for more than 10 years. The
rst article that correlated sensitization and headache was
published by Nature in 1996, which hypothesized - and
later validated - chemosensory similarity and sensitization of
meningeal sensory neurons with nociceptive neurons found
throughout the body.
While nociceptive pain is a physiological response to a
stimulus, severe enough to generate pain (as trauma, extreme
temperatures, inammation and infections), neuropathic pain
is a pathological status with abnormalities in the transmis-
sion and processing (as in post-traumatic, post-infectious or
post-ischemic painful neuropathy). Migraine, in the other
hand, is under the group of nociplastic pain, characterized
by pain mechanism dysfunction, since there is no anatomical
lesion that could explain the symptoms.
During the nal stages of a migraine attack as well as in
chronication period, the sensory neurons that innervate the
meninges synapse with second-order neurons of the trigeminal
caudate nucleus (TCN) in the brain stem. This leads to two
nociceptive properties: chemosensitivity and sensitization.
Chemosensitivity is characterized by a process in which a
neuron previously insensitive to a specic stimulus in its resting
state becomes sensitive to that stimulus in the presence of an
altered chemical environment. Sensitization is the process in
which the stimulus needed to generate a response decreases
over time, while the amplitude of the response increases
("peripheral" sensitization refers to the process that occurs in
neurons in the peripheral system and "central" sensitization,
the analogous process in the central nervous system).
The result of these changes is expressed by hyperalgesia
(exaggerated and intensied pain in response to a stimulus
that is supposed to cause lower intensity of pain) or allodynia
(painful response to a non-painful stimulus).
In migraine, sensitized nociceptors send stimuli of increasing
intensity (peripheral sensitization) to the spinal cord and
brainstem, which, if repeated, may lead to CS and additional
pain amplication. Peripheral sensitization in migraine is due
to dural neuroinammation and meningeal trigeminal noci-
ceptors activation. The beginning of this process may include
widespread cortical depression or autonomic dysfunction with
excessive parasympathetic activity.
CS is associated with abnormal neuronal excitability in the
TCN. Increasing stimuli expressed by the trigeminal nerve,
as a consequence of peripheral sensitization, triggers this
neuronal hyperexcitability. Other chemical disorders, such as
decreased magnesium and increased calcium and glutamate
are mediated by NMDA receptors and are also associated
with this change in TCN. Recent evidences suggest that CS
is maintained by glial cells activation surrounding the TCN,
generating multiple changes including the production of
In the present study, when evaluating BP-CSI Part A of each
subgroup, a higher average score is shown in patients with
chronic migraine in relation to episodic and control group
(mean: 47.0, 37.3 and 20.2, respectively). There are no known
studies comparing directly migraine with CS levels through
BP-CSI, but it can be assumed that there is a higher level of CS
in patients with chronic migraine, in relation to the episodic
group, and both in relation to the control group.
we can conclude that patients with episodic migraine have
lower levels of CS. This data is useful in the management and
treatment, because earlier identication of CSS may reduce
time, efforts and nancial resources in high-cost diagnostic
tests, invasive procedures and even surgeries. Through low
cost and time savings, the use of BP-CSI allows us to increase
diagnostic sensitivity and start treatment in advance, reducing
hospital costs and improving rates of response to treatment
and patient satisfaction.
However, our study had some weaknesses that need further
discussion. First of all, the samples were not paired by sex,
since the episodic and chronic migraine subgroups had twice
more women than the control group. One additional concern
was that the control group did not include any other sensitiza-
tion syndrome diagnosis other than migraine (like bromyal-
gia, irritable bowel syndrome, depression etc) which, in turn, is
listed in the BP-CSI Part B. Finally, some patients with episodic
or chronic migraine had previous treatment modalities such
as antidepressants and anticonvulsants, which could modify
the nal BP-CSI score.
We suggest that in the future, studies should include a higher
number of patients, selecting a better sample prole in each
Nihi MA, Santos PSF, Almeida DB
Central sensitization in episodic and chronic migraine
subgroup, in order to standardize the research and provide
unied results. Additionally, these studies should consider
other comorbidities not related to migraine and CS (which
could distort the perception of clinical manifestations) and
select migraine patients before pharmacological interventions
for a better analysis of the results.
CS in chronic migraine is a well-established phenomenon
and described in the literature. However, the present study
also shows evidences of mild CS in patients with episodic
migraine, evaluated in a private hospital specialized in neu-
rological disorders through the application of BP-CSI. Despite
the limitations of our study, scientic evidence in the previous
current literature did not show incontestable occurrence of CS
in patients with episodic migraine. The identication of this
disturbance is important for better management and early
control of treatment, reducing time, efforts and nancial re-
sources in high-cost diagnostic tests and invasive procedures.
Author's Contribution: MAN - Data Collection, Conceptualiza-
tion, Methodology, Writing - Preparation of the original, Writing
- Review and Editing; PSFS - Writing - Proofreading and Editing,
Supervision; DBA Writing, Proofreading and Editing, Supervision
Marco Antonio Nihi
1. International Association for the Study of Pain, 2019, accessed
13 August 2020, <http://iasp-pain.org> International Associ-
ation for the Study of Pain.
2. Yunus MB. Role of central sensitization in symptoms beyond
muscle pain, and the evaluation of a patient with widespread
pain. Best Pract Res Clin Rheumatol. 2007 Jun;21(3):481-97.
3. Latremoliere A, Woolf CJ. Central Sensitization: a generator of
pain hypersensitivity by central neural plasticity. J Pain. 2009
4. Jinks C, Jordan K, Croft P. Measuring the population impact
of knee pain and disability with the Western Ontario and
McMaster Universities Osteoarthritis Index (WOMAC). Pain.
2002 Nov;100(1-2):55-64.
5. Caumo W, Antunes LC, Elkfury JL, et al. The Central Sensitization
Inventory validated and adapted for a Brazilian Population:
psychometric properties and its relationship with brain-derived
neurotrophic factor. J Pain Res. 2017 Sep 1;10:2109-2122.
6. Mayer TG, Neblett R, Cohen H, et al. The development and
psychometric validation of the central sensitization inventory.
Pain Pract. 2012 Apr;12(4):276-85.
7. Bid D, Soni Neela C, Rathod Priyanshu V, et al. Content Va-
lidity and Test-Retest Reliability of the Gujarati Version of the
Central Sensitization Inventory. NJIRM 2016; Vol. 7(5) Sep-
8. Rapoport AM, Edvinsson, L. Some aspects on the pathophysiol-
ogy of migraine and a review of device therapies for migraine
and cluster headache. Neuro Sci. 2019 March: 1-2.
9. Pitance L, Piraux E ey al. Cross-cultural adaptation, reliability
and validity of the French version of the central sensitization
inventory. Manual Therapy 2016; 25 (Complete):e83-e84.
10. Epidemiology of Headaches 2012. International Association
for the Study of Pain.
11. GBD 2015 Neurological Disorders Collaborator Group. Global,
regional, and national burden of neurological disorders during
1990-2015: a systematic analysis for the Global Burden od Dis-
ease Study 2015. Lancet Neurol. 2017 Nov; 16(11):877-897.
12. The International Classification of Headache Disordes 3rd
13. Neblett R, Cohen H, Choi Y et al. The Central Sensitization
Inventory (CSI): establishing clinically signicant values for
identifying central sensitivity syndromes in an outpatient chronic
pain sample. J Pain. 2013 May; 14(5):43845.
14. Neblett R, Hartzell MM, Mayer TG et al. Establishing Clinically
Relevant Severity Levels for the Central Sensitization Inventory.
Pain Pract. 2017 Feb; 17(2):166-175.
15. Lipton RB, Bigal ME, Diamond M et al. Migraine prevalence,
disease burden, and the need for preventive therapy. Neurology
2007 Jan 30;68(5):343-9.
16. Burch RC, Buse DC, Lipton RB. Migraine: Epidemiology, Burden,
and Comorbidity. Neurol Clin. 2019 Nov; 37(4):631-649.
17. Charles A. The evolution of a migraine attack - a review of recent
evidence. Headache 2013 Feb;53(2):413-9.
18. Charles A. The pathophysiology of migraine: implications for
clinical management. Lancet Neurol. 2018 Feb;17(2):174-182.
19. Maniyar FH, Sprenger T, Schankin C et al. Photic hypersensi-
tivity in the premonitory phase of migraine-a positron emission
tomography study. Eur J Neurol. 2014 Sep;21(9):1178-83.
20. Maniyar FH, Sprenger T, Schankin C et al. The origin of nausea
in migraine-a PET study. J Headache Pain 2014 Dec 3;15:84.
21. Goadsby PJ, Knight YE, Hoskin KL. Stimulation of the greater
occipital nerve increases metabolic activity in the trigeminal
nucleus caudal and cervical dorsal horn of the cat. Pain 1997
22. Charles AC, Baca SM. Cortical spreading depression and
migraine. Net Rev Neurol. 2013 Nov;9(11):637-44.
23. Charles A. Migraine: a brain state. Curr Opin Neurol. 2013
24. Wattiez AS, Sowers LP, Russo AF. Calcitonin gene-related pep-
tide (CGRP): role in migraine pathophysiology and therapeutic
targeting. Expert Open Ther Targets. 2020 Feb;24(2):91-100.
25. Mathew NT. Pathophysiology of chronic migraine and mode of
action of preventive medications. Headache. 2011 Ju-Aug;51
Suppl 2:84-92.
26. Valfre W, Rainero I, Bergui M et al. Voxel-based morphometry
reveals gray matter abnormalities in migraine. Headache. 2008
27. Welch KM, Nagesh V, Aurora SK et al. Periaqueductal gray
matter dysfunction in migraine: cause or the burden of illness?
Headache. 2001 Jul-Aug;41(7):629-37.
28. Aurora SK, Barrodale PM, Tipton RL et al. Brainstem dysfunction
in chronic migraine as evidenced by neurophysiological and
positron emission tomography studies. Headache 2007 Jul-
29. Strassman AM, Raymond SA, Burstein R. Sensitization of men-
ingeal sensory neurons and the origin of headaches. Nature
1996 Dec 12;384(6609):560-4.
30. Dodick D, Silberstein S. Central sensitization theory of migraine:
clinical implications. Headache 2006 Nov;46 Suppl 4:S182-
31. Strassman AM, Levy D. Response properties of dural nociceptors
in relation to headache. J Neurophysiol. 2006 Mar;95(3):1298-
32. Costigan M, Woolf CJ. Pain: molecular mechanisms. J Pain
2000 Sep;1(3 Suppl):35-44.
33. Neblett R, Hartzell MM, Cohen H et al. Ability of the cen-
tral sensitization inventory to identify central sensitivity syn-
dromes in an outpatient chronic pain sample. Clin J Pain 2015