Temporal summation, conditioned pain modulation, pressure pain threshold and central sensitization symptoms in individuals with chronic migraine: cross sectional observational study

ABSTRACT

BACKGROUND AND OBJECTIVES  Chronic migraine is defined by attacks on 15 or more days per month, with at least eight of them presenting typical migraine characteristics, and is recognized as a central sensitization syndrome marked by somatosensory alterations and a pathophysiology that remains not fully understood. This study investigates the clinical presentation of somatosensory aspects in individuals with chronic migraine during the interictal phase compared to healthy individuals.

METHODS  This is a cross-sectional observational study conducted in individuals with chronic migraine and healthy individuals aged between 18 and 55 years. Measures: temporal summation (temporal summation test), conditioned pain modulation (conditioned pain modulation test), pressure pain threshold (algometer), central sensitization (Central Sensitization Inventory) and allodynia (12-item checklist of allodynia symptoms).

RESULTS  32 migraine individuals (MG) and 22 from the health control group (CG) were included in this study. In the temporal sum test, pain amplification showed a significant difference between groups MG and CG in all seconds analyzed. Pressure pain thresholds were significantly lower in the moments of three measurements in the MG compared to the CG in the conditioned pain modulation test. Pressure pain thresholds in the head, neck and right tibialis anterior muscles were significantly lower in the MG compared to the CG. Central Sensitization Inventory scores were equivalent to an average of 56/100 points, representing a severe level of these central sensitization symptoms with chronic migraine. Severe symptoms of allodynia were present in 52% of participants with chronic migraine.

CONCLUSION  When assessed in the interictal period, individuals with chronic migraine showed alterations in somatosensory aspects related to pain, identified by amplification of the magnitude of the pain response, deficits in endogenous pain inhibition mechanisms, profound mechanical hyperalgesia and allodynia.

Keywords:
Central nervous system sensitization; Chronic pain; Headache disorders; Migraine disorders; Pain measurement

HIGHLIGHTS

Chronic migraines are characterized by an amplification of the pain response, deficits in endogenous pain inhibition and mechanical hyperalgesia, with a high prevalence of symptoms of central sensitization and allodynia

Tools such as quantitative sensory tests map the somatosensory profile, deepening the understanding of the mechanisms underlying pain and aiding in the personalization of therapeutic strategies

Reduced efficiency in conditioned pain modulation, associated with cutaneous allodynia, demonstrates dysregulation in pain modulation mechanisms

RESUMO

JUSTIFICATIVA E OBJETIVOS  A migrânea crônica é definida por ataques em 15 ou mais dias por mês, com pelo menos oito deles apresentando características típicas de migrânea, sendo reconhecida como uma síndrome de sensibilização central marcada por alterações somatossensoriais e uma fisiopatologia que permanece não totalmente compreendida. Este estudo investiga a apresentação clínica dos aspectos somatossensoriais em indivíduos com migrânea crônica durante a fase interictal em comparação com indivíduos saudáveis.

MÉTODOS  Trata-se de um estudo transversal observacional conduzido em indivíduos com migrânea crônica e indivíduos saudáveis com idade entre 18 e 55 anos. Medidas: somação temporal (teste de somação temporal), modulação condicionada da dor (teste de modulação condicionada da dor), limiar de dor à pressão (algômetro), sensibilização central (Central Sensitization Inventory) e alodínia (lista de verificação de 12 itens de sintomas de alodínia).

RESULTADOS  Foram incluídos neste estudo 32 indivíduos com migrânea crônica (GM) e 22 no grupo controle (GC). No teste de somação temporal, a amplificação da dor apresentou diferença significativa entre os grupos GM e GC em todos os segundos analisados. Os limiares de dor à pressão foram significativamente menores nos momentos das três medidas no GM em comparação ao GC no teste de modulação condicionada da dor. Os limiares de dor à pressão nos músculos da cabeça, pescoço e tibial anterior direito foram significativamente menores no GM em comparação ao GC. Os escores do Inventário de Sensibilização Central foram equivalentes à média de 56/100 pontos, representando um nível grave desses sintomas de sensibilização central nos participantes com migrânea crônica. Sintomas graves de alodínia estavam presentes em 52% dos participantes com migrânea crônica.

CONCLUSÃO  Quando avaliados no período intericta, os indivíduos com migrânea crônica apresentaram alterações nos aspectos somatossensoriais relacionados à dor identificados por meio da amplificação da magnitude da resposta dolorosa, déficits nos mecanismos endógenos de inibição da dor, hiperalgesia mecânica profunda e alodínia.

Descritores:
Dor crônica; Medição da dor; Sensibilização do sistema nervoso central; Transtornos de cefaleia; Transtornos de migrânea

DESTAQUES

A migrânea crônica é caracterizada por uma amplificação da resposta à dor, déficits na inibição da dor endógena e hiperalgesia mecânica, com alta prevalência de sintomas de sensibilização central e alodínia

Ferramentas como os testes sensoriais quantitativos mapeiam o perfil somatossensorial, aprofundando a compreensão dos mecanismos subjacentes à dor e auxiliando na personalização das estratégias terapêuticas

A eficiência reduzida na modulação da dor condicionada, associada à alodínia cutânea, demonstra uma desregulação nos mecanismos de modulação da dor

INTRODUCTION

Primary headache is a type of headache whose etiology is unknown, it is characterized by hypersensitivity to stimuli and was considered the second leading cause of disability in 2016 by the Global Burden of Disease Study¹,² . According to the International Classification of Headaches, migraine consists of a chronic condition when it recurs on 15 days a month, of which at least 8 days have migraine characteristics, such as pain with moderate to severe intensity, pulsatile, unilateral and phobia of smells, sounds and lights¹ .

The clinical presentation of migraine is complex and multifaceted, with four phases: premonitory, aura, headache and postdrome, which can be linear, overlapping or cyclical³ . Furthermore, the period between attacks known as interictal, which is related to the absence of migraine symptoms⁴ .

Despite the exponential growth of studies about migraine in recent years, its pathophysiology is still not fully understood, but some mechanisms identified as likely responsible for the development and management of migraine crises⁵ . For a long time, changes in the vascular system justified the existence of crises, but recently other currents have come to consider migraine as a central sensitization syndrome, with the involvement and impairment of several body systems³,⁵ .

From the activation and involvement of several brain areas, whether triggering a migraine crisis, causing pain, or even in the presence of associated symptoms that occur during the duration of the crisis, given the inherent complexity of cases of chronic migraine, it is worth highlighting the aspects somatosensory factors involved in its pathophysiology and in the chronification process: temporal summation, conditioned pain modulation, pressure pain threshold, allodynic and central sensitization symptoms³,⁵ .

However, despite extensive research efforts, controversies persist regarding the alterations in parameters associated with the perception of both nociceptive and non-nociceptive stimuli throughout the cyclic phases of migraine. Notably, existing literature has primarily focused on the somatosensory aspects during the ictal and perictal phases, leaving gaps in our understanding of the interictal phase of chronic migraine⁶ .

Recent studies have contributed valuable insights in this area. An observational study explored profiles of patients with episodic migraine during the ictal/perictal phase, revealing distinct groups based on clinical and psychophysical variables⁶ . Similarly, another observational study investigated these profiles during the interictal phase, identifying heterogeneous patterns of pain sensitivity and functional impairment among patients with episodic and chronic migraine⁷ . Additionally, another observational study examined the intricate relationship between clinical and psychophysical characteristics across different phases of the episodic and chronic migraine cycle⁷ .

Despite this progress, further investigations are needed to elucidate the underlying mechanisms driving these observed variations and their implications for personalized strategies in an attempt to managing chronic migraine. Therefore, the aim of this study was to investigate the clinical presentation of somatosensory aspects in subjects with chronic migraine during the interictal phase compared to healthy subjects.

METHODS

Study design

This is an epidemiological, observational, comparative and cross-sectional study, in which individuals with a clinical diagnosis of chronic migraine were considered as the target population and compared with healthy individuals. This study considered and met the requirements of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)⁸ .

This study included individuals of both genders aged between 18 and 55 years, with a history of chronic migraine diagnosed by a qualified neurologist according to the criteria of the International Headache Society¹ .

In addition, individuals with other types of associated secondary headache, history of head and/or neck trauma, neurological diseases, psychiatric diseases, inability to understand instructions or consent for the study, severe respiratory diseases, and pregnancy were not included in the study, and with comorbidities that present symptoms of headache, such as uncontrolled high blood pressure and fibromyalgia.

Control group consisted of participants with a maximum of two episodes of headache in the last year who did not meet the criteria for migraine or any other type of chronic headache. Exclusion criteria for the control group were the same as those used for the migraine group. Additionally, individuals did not have any other type of pain in other body regions.

Procedures

The recruitment of participants was carried out through social networks (official website of the University, official laboratory pages on Instagram and Facebook, as well as by referral, from January 2019 to February 2020.

People who met the inclusion criteria and who did not have a clinical diagnosis were referred to a neurologist experienced in headache. After diagnostic consolidation, the volunteers were evaluated individually, as well as the individuals in the control group.

Two investigators underwent training and conducted a pilot study to standardize the evaluation using the instruments established for the research methodology. The evaluation proceeded as follows:

• Migraine group: temporal summation tests, conditioned pain modulation test, pressure pain threshold, central sensitization inventory and 12-item checklist of allodynia symptoms were performed.

• Control group: the evaluation was equivalent to that performed in the migraine group; however, the following variables were not applied: central sensitization inventory, and the 12-item checklist of allodynia symptoms.

It is worth mentioning that, in all evaluations carried out in the group of patients with migraine, they were in the interictal phase without headache or other symptoms. The assessment form consisted of sociodemographic data such as age, height, weight, body mass index, age at which migraine attacks began, history of the current illness, family history, the drugs used, associated illnesses and social history.

• Temporal summation (TS): consists of a quantitative sensory test, which seeks to verify the mechanism of constant and repetitive nociceptive nerve stimulation (wind-up) that results in an exacerbated response in the central nervous system, with an increase in the magnitude and frequency of this response⁹ . For this test, a digital pressure algometer (Impac^™, Paulínia, SP, Brazil; with an area of 1 cm²) was used with a pressure of 2.5 kg applied on the anterior surface of the patient's dominant forearm, 7.5 cm proximally to the distal crease of the wrist. After that, this continuous pressure was applied for 30 seconds, with four measurements related to pain intensity through an 11-point numerical scale, at the 1st second, 10th second, 20th second and 30th second¹⁰,¹¹ . The pressure of 2.5 kg was chosen based on specific protocols to evaluate sensitivity to mechanical stimulus and pain response. To ensure pressure adequacy and avoid excessive discomfort, the protocol was monitored and adjusted as necessary. Participants were instructed about the procedure and the pain scale, and adjustments were made so that the pressure was not enough to cause pain or was uncomfortable, always within ethical and safety limits¹² .

• Conditioned pain modulation (CPM): corresponds to the phenomenon in which the perception of pain at a site is inhibited in the face of a conditioned painful stimulus, based on the descending noxious inhibitory control mechanism or “pain inhibiting pain”¹³ . The initial pressure pain threshold (PPT) was measured using a digital pressure algometer (Impac^™, Paulínia, SP, Brazil; with an area of 1 cm²), positioned on the anterior surface of the dominant forearm, 7.5 cm proximally to the distal crease of the wrist. Then, an ischemic compression was performed on the individual's contralateral upper limb, using a sphygmomanometer (Mikatos^™, Embu, SP, Brazil) positioned with the lower edge of the device 3 cm proximal to the cubital fossa and a pressure of 270 mmHg maintained. Then, the individual was asked about the intensity of pain from the numerical scale of 11 points, after reporting pain 4, a new measurement of the PPT was performed in the dominant forearm simultaneously with the ischemic compression. Then, five minutes after the end of the procedure, the PPT was measured again.

• Pressure pain threshold (PPT): represents the initial pain sensitivity reported by the patient and can be measured using a mechanical or electronic pressure algometer¹⁴ . The thresholds were evaluated using a previously calibrated digital pressure algometer (Impac™, Paulínia, SP, Brazil; with an area of 1 cm²). Participants were instructed to report when the pressure sensation became painful. With the patient in the supine position, three bilateral measurements evaluated in the muscle bellies of the following muscles (primary PPT): A – temporal (muscle belly), B – frontal (2 cm above the midpoint of the supraorbital arch), C – masseter (1 cm superior and 2 cm anterior to the mandibular angle), D – sternocleidomastoid (SCOM) and E – upper trapezius muscle. The secondary PPT evaluated in the right anterior tibial muscle¹⁵,¹⁶ .

• Central sensitization: described as a phenomenon involving hypersensitivity of the central nervous system¹⁷ . The Central Sensitization Inventory (CSI) was validated for Portuguese in 2017; this instrument evaluates the presence of central sensitization in patients with chronic pain in clinical practice and scientific research¹⁸ . It consists of two parts, the first part consists of 25 items that generate a final score from 0 to 100 points, while the second part is related to diagnoses already closed, the higher the scores, the more likely the involvement of mechanisms consistent with the diagnosis.

• Allodynia symptom: presents itself from a stimulus that normally does not cause pain, generating a painful sensation; this symptom can be pointed out as a predictive factor of migraine chronification. The 12-item Allodynia Symptom Checklist (ASC-12) is a quick and easy-to-administer questionnaire, validated for the Brazilian version in individuals with migraine¹⁹ . It assesses symptoms of cutaneous allodynia and categorizes them into severity levels. It consists of 12 questions and their sum provides a score from 0 to 24, where each question is scored as follows: “this situation does not apply to me”, “rarely”, or “no, never” = 0; “sometimes yes, sometimes no” = 1; “most of the time” = 2. Thus, it is classified according to severity, where: no allodynia (0-2 points); mild allodynia (3-5 points); moderate allodynia (6-8 points); severe allodynia (9 or more points).

Bias

To minimize the biases involved in this type of study, the following precautions were considered:

• Observer/interviewer bias: the same observer assessed all individuals included in the study using validated tools and questionnaires; however, there was no blinding regarding exposure and outcome.

• Recall bias: participants were blinded to the study hypothesis, in addition, cases and controls were equally encouraged to recall past events, and both assessments/interviews of cases and controls were carried out in the same room and with the same controlled environment.

• Performance bias: in both groups the interviewer/evaluator maintained the standard posture during the study stages.

• Detection bias: in both groups the same assessment instruments and questionnaires were used, except those tools and questionnaires that were specific for the assessment of individuals with chronic migraine.

• Confusion bias: to avoid this type of bias the study design outlined the eligibility criteria, pairing and stratification of the sample.

Sample size

Sample size was determined based on the mean and standard deviation (SD) taken from a study that compared PPTs in the trapezius muscle between individuals with migraine and healthy participants²⁰ . PEPI-for-Windows™ (WinPEPI) software was used in the Sample Size domain, comparing two groups (radius B:A=1), using mean (SD), SD migraine group (A)=2.5; SD healthy individuals (B)=2.8, of the variable PPT, assuming a clinically significant difference of 20% in the PPT. The alpha domain was 5%, assuming a significance of 0.05 and the beta domain 80%. The required sample was 56 subjects (28 in group A and 28 in group B), with an expected accuracy of approximately 95% confidence interval for mean difference (D)= D - 1.405 to D + 1.405.

Ethical aspects

This project was approved by the Ethics Committee for Research with Human Beings of the Federal University of Sergipe, CAEE: 08310319.1.0000.5546, under opinion number 3.303.828. All subjects included in this study signed the Free and Informed Consent Term (FICT) prior to the evaluation, in compliance with Resolution 466/12 of the Brazilian Health Council (Conselho Nacional de Saúde - CNS).

Statistical analysis

The collected data was transferred to Microsoft^® Office Excel, 2018 data sheets. The software used to perform the statistical analyzes was GraphPad Prism version 6.0 (San Diego, CA, USA). Values were expressed as mean, standard error of mean and frequency. All variables were tested for normality using the Shapiro-Wilk test. Data that followed a normal distribution were analyzed using the t test for independent measures, whereas non-parametric data were compared using the Mann-Whitney test. Categorical variables were evaluated using Fisher's Exact test and the Chi-square test, according to their specificities.

For variables with several measures within the same group over a previously stipulated period (temporal summation and conditioned pain modulation), ANOVA test was also used for repeated measures followed by Bonferroni post hoc when the data were parametric (conditioned modulation of pain; pain strata mild pain and moderate pain) and Friedman followed by Tukey's post hoc for those non-parametric data. In all comparisons, statistically significant differences were considered when the p value in the analysis was less than 0.05 (p<0.05), indicating a minimal chance of the event occurring due to chance.

RESULTS

A total of 69 eligible volunteers were recruited through phone screening, of whom thirty-five were excluded based on pre-established criteria. This resulted in the recruitment of 34 volunteers, but two did not attend the assessments. Consequently, 32 individuals with migraines were evaluated. Therefore, total sample for this study consisted of 32 migraine patients (MG) and 32 healthy control volunteers (CG). Sociodemographic characteristics of participants from both groups are described in Table 1.

Table 1
Sociodemographic characterization of the sample.

Variables	Migraine Group (n=32)	Control Group (n=22)	p-value
Gender
Female	28 (87.5%)	18 (81.8%)	0.701c
Male	4 (12.5%)	4 (18.2%)
Age (years)	33.84±1.47	29.27±0.93	0.047b
Weight (kg)	64.64±2.94	66.19±2.13	0.514b
Height (m)	1.64±0.01	1.63±0.01	0.713a
BMI (kg/m2)	23.73±0.77	24.73±0.73	0.279b

• Data presented as mean, standard error of mean and percentage. kg: kilogram; m: meters; kg/m²: kilogram divided by meter squared; n: number of individuals per group; BMI = body mass index; ^at test for independent measures; ^bMann-Whitney test for independent measures; ^cChi-square test.

Variables

In the temporal summation test, pain amplification showed a significant difference between the migraine group compared to the control group in all analyzed timepoints, being in normal patterns in the control group and exacerbated in the migraine group. The following values were found: in the first second, MG 3.25±0.42 and CG 1.59±0.35 with p=0.009; in the twelfth, MG 4.65±0.52 and CG 2.18±0.38 with p=0.002; in the twenty second, MG 5.15±0.53 and CG 3.09±0.47 with p=0.009; and in the thirty second, MG 5.84±0.53 and CG 3.40 ±0.50 with p=0.003 (Figure 1).

Figure 1
Temporal summation test through pain intensity at sequential times (1^st second, 10^th second, 20^th second and 30^th second) between control group and migraine group. Data expressed as mean and standard error of the mean. *Different from the control group, Mann-Whitney test for independent samples (p<0.05). **Different from the control group, t-test for independent samples (p=0.009).

In the conditioned pain modulation test, PPTs were significantly lower at all three measurement times in the migraine group compared to the control group. Before ischemic compression, the GM subjects had 3.59±0.31 kgf, while CG had 5.91±0.51 kgf, with p= 0.003; during ischemic compression, GM had 4.59±0.32 kgf and CG 7.44±0.54 kgf, with p= 0.001; after five minutes of ischemic compression, GM had 3.86±0.33 kgf) and CG had 5.68±0.44 kgf, with p=0.001 (Figure 2).

Figure 2
Conditioned pain modulation measured using pressure pain threshold (kgf) between control and migraine groups. Data expressed as mean and standard error of the mean. *Mann-Whitney test for independent samples, different from the control group assuming the highest p value, in this case p=0.003.

Pressure pain thresholds in the muscles of the head, neck and right tibialis anterior muscle were significantly lower in the migraine group compared to the control group (Figure 3).

Figure 3
Pressure pain threshold in kgf in the head and neck muscles and in the tibialis anterior muscle between the control group and the migraine group. SCOM = sternocleidomastoid. Data expressed as mean and standard error of the mean. *Different from the control group for all assessed muscles, Mann-Whitney test (p<0.05).

Scores found through the Central Sensitization Inventory were equivalent to 56 points on a score from 0 to 100. Allodynia verified by the 12-item list of allodynia symptoms was applied only to 25 patients out of 32 patients with chronic migraine and demonstrated that 52% had severe allodynic symptoms, 24% moderate allodynic symptoms, 4% mild allodynic symptoms and only 20% had no allodynic symptoms.

DISCUSSION

The main findings of this study can be summarized as follows: people with chronic migraine exhibited amplification of the magnitude of pain response, deficits in endogenous pain inhibition mechanisms and decreased pressure pain thresholds or mechanical hyperalgesia when compared to control individuals. In addition, it was possible to identify severe levels of central sensitization and severe allodynic conditions in people with chronic migraine.

Quantitative sensory tests are used to assess somatosensory functions and help to understand the clinical neurophysiology of pain⁵,²¹ . In this study, three quantitative sensory tests were used, namely, temporal summation, conditioned pain modulation and pressure pain thresholds, these contribute to the mapping of the somatosensory profile in people with chronic migraine in the interictal phase and control subjects.

This study observed that people with chronic migraine presented an amplification of the painful response to a repetitive stimulus through the pain temporal summation mechanism. In agreement with previous studies with experimental and daily stimuli²² , which presented similar results, however using different protocols, such as the use of von Frey filaments and the visual analog pain scale.

Persons with chronic migraine exhibited less efficient conditioned pain modulation mechanism than healthy controls in this research. These findings are suggestive of the presence of deregulation of pain modulatory mechanisms. In this context, pain descending inhibitory pathways may be deficient in these people, leading to increased pain perception with a subsequent process of hyperactivation of pain facilitation pathways, in line with data highlighted in reviews previously found in the literature⁵,²¹,²³ .

Furthermore, the individuals with chronic migraine showed increased mechanical hyperalgesia compared to control subjects in the sample of this research. Commonly, this assessment of the mechanical pain threshold has been performed in the head and neck muscles, representing primary and secondary hyperalgesia and consequent peripheral sensitization process. However, few studies, like the present study, have evaluated the pressure pain threshold in regions distal to the main pain area, representing tertiary hyperalgesia, reaffirming the presence of the central sensitization process²⁴ .

In this study, people with migraine had an average score above 40 points, indicating moderate levels of severity for central sensitization symptoms²⁵ . So far, this study observed the need for more studies that assess the presence of central sensitization symptoms through CSI in chronic migraine patients in order to carry out compilations of future results in scientific research with high methodological rigor.

This study noticed a high prevalence of allodynic symptoms, especially in individuals with moderate to severe levels of severity. Clinically, it is important to recognize this symptom of cutaneous allodynia, as it is a known factor in the chronification process and can influence the poor response to some therapeutic modalities, such as neuromodulation, electrical stimulation, and manual therapies due to contact in the region²⁶ .

Some limitations can be listed in this study, first care must be taken when extrapolating these data to the male population, since this population corresponded to the minority of the sample. Likewise, migraine is associated with alterations in the female hormonal cycle, and this study did not record the phase of the menstrual cycle at the time of evaluation. Another point to consider is the format of the study itself since it makes it impossible to establish a cause and consequence relationship between the results found due to the cross-sectional nature of this study. Finally, although two trained assessors performed assessments, they not blinded to the chronic migraine diagnosis and control subjects.

Strengths of this study include the population of people with chronic migraine well established and provided through a clinical diagnosis. In this study, all description and design followed the recommendations of STROBE tool⁸ . Furthermore, a clinical neurophysiological approach to pain was used through quantitative sensory tests described in the literature²¹ . Clinically, the responses observed in the sample of this study reinforce that people with chronic migraine present somatosensory disorders even in the absence of crises, implying central and peripheral symptomatology.

The findings of this study provide valuable information for clinicians in the management of chronic migraine. The identification of amplification of the pain response, deficits in endogenous pain inhibition, and mechanical hyperalgesia highlights the need for comprehensive therapeutic approaches. Quantitative sensory testing offers a useful tool for mapping the somatosensory profile, allowing for a more in-depth understanding of the clinical physiology of pain. The observation of reduced efficiency in conditioned pain modulation suggests possible dysregulations in pain modulating mechanisms, indicating specific therapeutic pathways. The high prevalence of symptoms of central sensitization and allodynia highlights the need to consider these aspects when formulating treatment strategies. Recognizing the presence of cutaneous allodynia is crucial for appropriate therapy selection as it may influence the response to specific therapeutic modalities.

Future studies may consider the presence of a greater description of migraine-related characteristics, such as intensity, frequency, duration, and associated symptoms. In addition, this study can support future intervention studies focused on the aspects addressed.

CONCLUSION

Individuals with chronic migraine have increased pain response magnitude, deficits in endogenous pain inhibition mechanisms and decreased pressure pain thresholds when compared to control individuals. In addition, it was possible to identify severe levels of central sensitization and severe allodynic conditions in people with chronic migraine.

• Sponsoring sources:
  The authors received the following financial support for the research, authorship and/or publication of this article: Foundation for the Support of Research and Technological Innovation of the State of Sergipe (FAPITEC/SE); National Council for Scientific and Technological Development (CNPq); Coordination for the Improvement of Higher Education Personnel, Brazil (CAPES), Financial Code 001.

References

• ¹ International Headache Society. Headache Classification Committee. The International Classification of Headache Disorders, 3rd ed. (beta version). Cephalalgia. 2013;33(9):629-808. http://doi.org/10.1177/0333102413485658 PMid:23771276.
  » http://doi.org/10.1177/0333102413485658
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Edited by

• Associate editor in charge:
  Renato Leonardo de Freitas https://orcid.org/0000-0003-1799-5326

Publication Dates

• Publication in this collection
  12 May 2025
• Date of issue
  2025

History

• Received
  02 Feb 2024
• Accepted
  02 Dec 2024