Headache Medicine 2020, 11(4):85-89 ISSN 2178-7468, e-ISSN 2763-6178

ASAA

DOI: 10.48208/HeadacheMed.2020.25

Headache Medicine

Original

Central sensitization in episodic and chronic migraine

Marco Antonio Nihi¹ , Paulo Sergio Faro Santos¹, Daniel Benzecry Almeida²

Neurological Institute of Curitiba, Neurology - Curitiba, PR - Brazil

Neurological Institute of Curitiba, Neurosurgery - Curitiba - PR - Brazil

Abstract

Introduction

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.

Objectives

To evaluate the occurrence and severity of CS in patients with episodic and chronic migraine,

comparing with a control group.

Methods

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.

Results

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.

Conclusions

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

marco.nihi@gmail.com

Edited by

Mario Fernando Prieto Peres

Keywords:

Migraine

Central sensitization syndrome

Central sensitization inventory

Episodic migraine

Chronic migraine

Received: November 14, 2020

Accepted: November 30, 2020

ASAA

Nihi MA, Santos PSF, Almeida DB

Central sensitization in episodic and chronic migraine

Introduction

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.

This

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.

2,3

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.

2,4

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).

3,4

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.

The

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

procedures.

5,6,7

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.

Methods

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.

ASAA

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

signicance.

Results

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)

Sex

Female

66%

EM 77.1%

CM 86.1%

CG 33..3%

Male

34%

EM 22.9%

CM 13.3%

CG 66.7%

Age group

(years)

15-30 46%

30-50 41%

50-70 12%

>70 1%

Schooling

High school

15%

EM 22.9%

CM 16.7%

CG 3.3%

University education

85%

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

ASAA

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

Discussion

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

procedures.

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.

Factors

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.

ASAA

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).

25,31

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

prostaglandins.

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.

Furthermore,

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

ASAA

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.

Conclusion

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

https://orcid.org/0000-0002-5367-0214

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