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Pain sensitivity in relation to frequency of migraine and tension-type headache with or without coexistent neck pain: an exploratory secondary analysis of the population study

  • Sait Ashina ORCID logo EMAIL logo , Lars Bendtsen ORCID logo , Rami Burstein ORCID logo , Afrim Iljazi , Rigmor Hoejland Jensen ORCID logo and Richard B. Lipton ORCID logo
Published/Copyright: September 26, 2022
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Scandinavian Journal of Pain
From the journal Scandinavian Journal of Pain Volume 23 Issue 1

Abstract

Objectives

We aimed to investigate whether coexistent self-reported neck pain influences cephalic and extracephalic pain sensitivity in individuals with migraine and tension-type headache (TTH) in relation to diagnosis and headache frequency.

Methods

A population of 496 individuals completed a headache interview based on ICHD criteria, providing data collected by self-administered questionnaires, assessments of pericranial total tenderness score (TTS) and pressure pain thresholds (PPT). Stimulus-response (SR) functions for pressure vs. pain were recorded. Presence of neck pain in the past year was assessed by the self-administered questionnaire. We categorized participants by primary headache type. We also categorized participants into 3 groups by headache frequency: chronic (≥15) or episodic (<15 headache days/month) headache and controls. TTS, PPTs and the area under the SR curve were compared between subgroups using Generalized Linear Models with pairwise comparisons controlling for age and sex.

Results

Individuals with chronic followed by episodic headache had higher TTS than controls (overall p≤0.001). The difference between chronic and episodic headache subgroups was significant in the group with neck pain (p≤0.001) but not in the group without neck pain. In individuals with neck pain, mean TTS was higher in coexistent headache (migraine and TTH), 23.2 ± 10.7, and pure TTH, 17.8 ± 10.3, compared to pure migraine, 15.9 ± 10.9 and no headache 11.0 ± 8.3 (overall p<0.001). Temporal and finger PPTs did not statistically differ among the chronic headache, the episodic headache and controls in individuals with and without neck pain. Temporalis and trapezius SR-functions showed that tenderness was increased in individuals with chronic headache to higher degree than in those with episodic headache, and more so in those with neck pain.

Conclusions

Coexistent neck pain is associated with greater pericranial tenderness in individuals with chronic headache and to a lesser degree in those with episodic headache. Sensitization may be a substrate or consequence of neck pain and primary headache, but a longitudinal study would be needed for further clarification.

Keywords: central sensitization; comorbidity; headache; neck pain; pain threshold; peripheral sensitization; population; tenderness

Introduction

Neck pain is common global problem with one year period prevalence rate ranging from 4.8% to 79.5% in the general population depending on applied methodology [1], [2], [3]. Chronic neck pain is associated with substantial disability [3, 4] and is associated with both migraine and tension-type headache (TTH) [1, 5], [6], [7], [8], [9], [10], [11]. TTH followed by migraine are the two most common and disabling primary headache disorders [12, 13]. One-year prevalence of migraine ranges from 10 to 15%; for TTH estimates range from 38% to 78% [14], [15], [16], [17]. In individuals with migraine, neck pain can be a feature of the premonitory phase, the headache phase or the post-dromal phase, or can occur outside the context of a migraine attack. We previously demonstrated that self-reported coexistent neck pain was significantly more frequent in those with TTH and migraine than in individuals with no headache [1]. There was also a positive correlation between number of days with TTH or migraine per year and number of days with neck pain per year [1]. Moreover, we showed that individuals with neck pain had greater pain sensitivity than those free of neck pain based on higher pericranial total tenderness scores (TTSs) as well as lower cephalic and extracephalic pressure pain thresholds (PPTs). After adjusting for demographic variables and for the presence of migraine and/or TTH, the difference in PPTs was not statistically significant [1]. In contrast, the presence of a higher degree of tenderness in pericranial tissues and muscles, including neck muscles, in individuals with coexistent neck pain when compared to controls probably indicates peripheral or central sensitization or both. Similarly, in previous studies [18], lower PPTs in the neck region were reported in individuals with non-traumatic neck pain compared to those without neck pain where findings of lower PPT findings in tibialis anterior or thigh regions were inconsistent.

The disability due to neck pain is common in patients with migraine and TTH [19], [20], [21]. Neck pain may be directly involved in the pathophysiology of both migraine and TTH [22, 23], as a manifestation of trigeminocervical complex activation or as an activator of trigeminocervical complex neurons through the upper cervical roots.

In the current exploratory analysis, we aimed to assess whether the coexistent neck pain in individuals with migraine and TTH influences pain sensitivity and leads to peripheral or central sensitization as indexed by increased pericranial TTS, lower cephalic and/or extracephalic PPTs and increased stimulus-response (SR) functions for pressure vs. pain.

Methods

Study population

This study is an exploratory secondary analysis of a Danish population-based study scheduled and conducted at the Research Center for Prevention and Health and the Danish Headache Center, University of Copenhagen, Glostrup Hospital. The methods of this study have been described in detail elsewhere [1, 16, 24, 25].

In 1989, 1,000 residents in the County of Copenhagen, aged 25–64 years, were randomly chosen from the Danish Civil Registration System. All residents in Denmark are registered in the Danish Civil Registration System with a unique 10-digit code. Therefore, this sampling method ensured the selection of a random sample of the general population. Of 975 eligible subjects, 740 (76%) participated. The age and gender distribution of the participants was representative of the cohort and of the background population.

In 2001, a combined cross-sectional and follow-up study was conducted. A follow-up study of the cohort from 1989 was conducted including all subjects who in 2001 were alive, residing in Denmark, and capable of answering written and verbal questions. No intervention was made in the follow-up period. All eligible 1,000 subjects in the 1989 cohort, now aged 37–76 years, were identified through the Danish Civil Registration System and invited to participate. In addition, 300 individuals, new to the study, were selected using research criteria similar to the 1989 study. One difference was that the age range was limited to 25-36 years among the new 2001 recruits. Thus, a total of 1300 individuals were invited participated in this cross-sectional study in 2001.

The current exploratory analysis was conducted in the populations sample from the 2001 cross-sectional study. All individuals were invited to participate in a headache interview and a clinical examination. If subjects did not respond to the invitation, they were contacted and asked to complete a headache interview by telephone. Those who participated in the clinical examination were included in the quantitative sensory testing (QST). The invitation letter with the purpose of the study was sent. If no response was obtained, the telephone headache interview was attempted by physician (Ann C Lyngberg) and in this case no clinical examination was performed. All interviews and examinations throughout the 2001 survey, including the telephone interviews, were conducted between May 2001 and April 2002. The follow-up/cross-sectional study in 2001 used the same procedure and questions as the original 1989 study to optimize data comparability on the two testing occasions. The study population was representative of Danish population with respect age, sex and employment status with exception of self-employment such as fishing and farming that was underrepresented [25]. The study was approved by the Ethical Committee for Copenhagen County and by the Danish Data Protection Agency. Informed consent was obtained from individuals before participation.

Self-administered questionnaire

The self-administered questionnaire was administered in Danish and included questions successfully used in previous population studies [1, 25]. The questionnaire obtained information about socio-demographic factors, lifetime history of pain and psychiatric conditions and symptoms: low back pain, spine disease, rheumatic disease, fibromyalgia, depression and anxiety disorder. See next section for neck pain assessment.

Neck pain assessment

The coexistent neck pain was assessed by the self-administered questionnaire. Frequency of self-reported neck pain in the past year (1-year prevalence) was assessed. Response options were: 0 days, 1–7 days, 8–14 days, 15–30 days, 31–100 days, 101–179 days, and 180 or more days. For the analysis, study participants were categorized with (1 or more days per year) and without 1-year prevalence of neck pain. Neck pain (in Danish – “nakkesmerter”) in our questionnaire referred to the pain in the back of the neck or the posterior neck region.

Headache case definitions

The headache interviews were designed to assess the clinical features specified in the first edition of the International Classification of Headache Disorders (ICHD-1) [26], with an emphasis on migraine and TTH. The interviewer in 2001 had no knowledge of the headache diagnoses from 1989. The telephone interviews were conducted with the same diagnostic criteria (ICHD-1), interviewer, data collection period, interview questions and sequence as the face-to-face interviews. ICHD-1 criteria for migraine and TTH used in headache interview are fundamentally the same in the third edition of the International Classification of Headache Disorders (ICHD-3) [27] and thus no differences in classifications would be expected at the first digit level. Participants were asked about the number of days with TTH and migraine in the past year with 7 response options: “0 days”, “1–7 days”, “8–14 days”, “15–30 days”, “31–100 days”, “101–179 days”, “180 days or more”. For the analyses, migraine and TTH diagnoses were therefore given according to ICHD-3 except for Criteria E because neurological examination was not conducted in those individuals who were interviewed only by telephone. The infrequent episodic TTH was defined as headache occurring 14 or fewer days per year in our study. The no headache group included individuals who had either no primary headache and/or with infrequent episodic TTH (ETTH) (<12 headache days per year meeting criteria for TTH). We could not identify individuals with chronic migraine diagnosis with headache frequency response categorizes used in our questionnaire. Thus, we categorized participants with headache into 2 alternative groupings: (1) pure migraine, pure TTH, vs. coexistent headache (migraine and TTH) vs. other categories; and (2) episodic headache (<15 any headache days per month) and chronic headache (≥15 any headache days per month), no headache/infrequent episodic TTH.

Pain perception assessment

The participants were examined sitting in a comfortable dental chair with headrest. QST was performed by specially trained nurse using standardized methods. The participant’s headache history was not available to the nurse.

Pericranial tenderness by manual palpation 

To examine local tenderness the palpometer was used to train the examiner to exert a palpation pressure of moderate intensity (140 U). The palpometer has previously been described in detail and proved to be reliable [28]. Pericranial tenderness was assessed by palpation of eight pairs of muscle and tendon insertions. The tenderness was scored according to the Total Tenderness Score (TTS) on a 4-point (0–3) scale [28]. TTS was calculated by summing the scores from the 8 right- and left-sided locations with maximum possible score=48.

Pressure pain thresholds 

Pressure pain thresholds (PPTs) were assessed by an electronic pressure algometer (Somedic AB, Stockholm, Sweden) with a circular stimulation probe (0.5 cm2) and a pressure loading rate of 0.68 N/s was used [29]. PPTs were measured at the dorsum of the second (index) finger and at the anterior part of the temporal muscle, 2 cm behind the lateral orbital margin and 2 cm above the orbito-temporal line, at the non-dominant side. The PPT (in kPa) was defined as the pressure at which the sensation changed from pressure alone to a combination of pressure and pain. Measurements were performed alternately in the temporal region and in the finger with intervals of approximately 60 s. A mean value of three measurements on each location was used for determination of the individual PPT.

Stimulus-response functions for pressure pain 

SR functions for pressure vs. pain were recorded during pressure-controlled palpation. This method was previously proved to be reliable for tenderness assessment [30]. The participants were palpated at the temporalis and trapezius at the non-dominant side. Palpation was performed with 7 different pressure intensities in random order in the range from 80 to 200 U. At each pressure intensity, the participant reported the corresponding pain on a visual analogue scale (VAS) blinded for the observer. The degree of tenderness elicited in each subject was calculated as the area under the stimulus-response curve (AUC) is according to the trapezium rule [31].

Statistical analysis

Data are presented as frequency counts with percentages or means and standard deviations (SD) unless specified otherwise. We used Shapiro–Wilk test to determine whether the continuous variables were normally distributed. Mann–Whitney test was used to test recordings for paired observations because variables of interest were not normally distributed. Spearman’s test was used for calculation of correlation coefficients, r. TTS, PPTs and AUCs were compared between headache and no headache groups using Generalized Linear Models (GLM) analysis controlling for the effect of covariates: age (<50; ≥50 years) and sex. Additional adjustments for headache present during examination/QST day or coexistent headache were made. Pairwise comparisons with Bonferroni correction were performed to compare outcome variables between groups. Individuals with missing data were excluded from the analyses. Two-tailed p values were calculated. Five percent was accepted as the level of significance. Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 25.0 and 28.0, Armonk, NY, USA.

Results

Study sample

Of total 1,300, 848 (65.2%) participated in the headache interview. Altogether, 555 subjects participated in the face-to-face interview and 293 in the telephone interview. A total of 797 of 848 study participants (94.0%) provided data on variables of interests including age, sex, education, self-reported health, neck pain and other pain-related and psychiatric comorbidities/symptoms. A total of 545 individuals (68.4%) reported neck pain in the past year (one-year relative frequency) [1]. Only in individuals with neck pain in the past year, lifetime self-reported spine disease and depression rates were significantly more frequent in those also reporting primary headache (migraine and/or TTH) comparted to those with no headache (36.0% vs. 27.4%, p=0.03, and 17.1% vs. 8.1%, p=0.002, respectively).

Out of 797 participants, 496 (62.2%) also participated in the pain perception assessment/QST. QST participants did not differ from non-participants in sex (p=0.19) but were older than non-participants (50.7 ± 13.7 vs. 46.5 ± 13.8 (p<0.001). Headache diagnoses categorized by the report of coexistent neck pain in the past year and their frequencies in our study sample are presented in Table 1. A total of 21 out of 31 participants (67.7%) with chronic headache had coexistent migraine and TTH. In episodic headache subgroup, a total of 52 out of 168 participants (31.0%) had coexistent migraine and TTH.

Table 1:

Headache diagnoses categorized by report of coexistent neck pain in the past year in the study sample (n=496).

Coexistent neck pain
Yes (n=353) No (n=143)
Headache by frequency
No headache 181a 116
Episodic headache 148 20
Chronic headache 24 7
Headache by type
No headache 181a 116
Pure migraine 30 10
Coexistent headache 65 8
Pure TTH 77 9

  1. TTH, tension-type headache. aOnly180 individuals with no headache had measured temporal and finger pressure pain thresholds.

Pericranial tenderness

Total tenderness score by headache frequency

In individuals with neck pain, mean TTS was 22.6 ± 11.4 in chronic headache, 18.2 ± 10.3 in episodic headache and 11.0 ± 8.3 in no headache (Figure 1a). After adjusting for age and sex, mean TTS was significantly higher in chronic headache and episodic headache compared to no headache (p<0.001 and p<0.001 respectively), and between chronic and episodic headache groups (p<0.001). These differences remained significant after additional adjustment for headache on the examination day (p<0.01). After adjustment for age, sex, coexistent headache, mean TTS was only significantly higher in chronic headache compared to episodic headache and no headache groups (p=0.01 and p<0.001 respectively).

Figure 1: (a)–(c) Mean total tenderness score, pressure pain thresholds (kPa) in temporalis and finger (± SEM) according to headache frequency and coexistent neck pain in the past year. Generalized Linear Models (GLM) analysis controlling for the effect of covariates: age (<50; ≥50 years), sex. Pairwise comparisons with Bonferroni correction were performed to compare outcome variables between groups. SEM, standard error of mean; NS: p>0.05, *: p≤0.05, **: p≤0.01, ***: p≤0.001. Only p values for significant pairwise comparisons are shown.
Figure 1:

(a)–(c) Mean total tenderness score, pressure pain thresholds (kPa) in temporalis and finger (± SEM) according to headache frequency and coexistent neck pain in the past year. Generalized Linear Models (GLM) analysis controlling for the effect of covariates: age (<50; ≥50 years), sex. Pairwise comparisons with Bonferroni correction were performed to compare outcome variables between groups. SEM, standard error of mean; NS: p>0.05, *: p≤0.05, **: p≤0.01, ***: p≤0.001. Only p values for significant pairwise comparisons are shown.

In individuals without neck pain, mean TTS was 16.1 ± 11.6 in chronic headache, 13.0 ± 9.2 in episodic headache and 7.1 ± 7.0 in no headache (Figure 1a). After adjusting for age and sex, mean TTS was significantly higher in chronic headache and episodic headache compared to no headache group (p=0.022 and p=0.019 respectively). These differences did not remain significant after additional adjusting for headache on the examination day or coexistent headache. Differences between the chronic and episodic headache groups without neck pain were not significant.

Total tenderness score by headache type

In individuals with neck pain, mean TTS was higher in coexistent TTH and migraine headache, 23.2 ± 10.7, and pure TTH, 17.8 ± 10.3, compared to pure migraine, 15.9 ± 10.9 and no headache 11.0 ± 8.3 (overall p<0.001, adjusted for age and sex), (Table 2). Only the age- and sex-adjusted differences between coexistent headache and pure migraine (p=0.002), coexistent headache and no headache (p<0.001) and pure TTH and no headache (p<0.001) were significant. These differences remained significant after additional adjusting for headache on the examination day.

Table 2:

Total tenderness scores and pain thresholds by headache type categorized by report of coexistent neck pain in the past year (n=496).

Coexistent neck pain
Yes (n=352) No (n=143)
Total tenderness score
No headache 10.99 (8.26) 7.10 (6.99)
Pure migraine 15.90 (10.95) 10.30 (7.39)
Coexistent headache 23.18 (10.70) 19.00 (7.87)
Pure TTH 17.83 (10.31) 13.00 (12.21)
Pressure pain threshold – temporal muscle
No headache 244.79 (109.47) 254.94 (102.3)
Pure migraine 234.07 (103.41) 251.87 (116.01)
Coexistent headache 209.36 (94.82) 192.42 (73.54)
Pure TTH 217.35 (92.43) 223.04 (89.24)
Pressure pain threshold – finger
No headache 299.41 (140.39) 315.80 (141.01)
Pure migraine 329.20 (182.86) 304.00 (116.84)
Coexistent headache 274.90 (137.54) 273.50 (91.21)
Pure TTH 272.74 (135.40) 348.52 (146.18)

  1. Values are means ± standard deviation. TTS, total tenderness score; PPT, pressure pain thresholds (kPa); TTH, tension-type headache.

In individuals without neck pain, mean TTS was significantly higher in coexistent headache, 19.0 ± 7.9, and pure TTH, 13.0 ± 12.2, compared to pure migraine, 10.3 ± 7.4 and no headache 7.1 ± 7.0 (overall p<0.001, adjusted for age and sex), (Table 2). Only the age- and sex-adjusted difference between coexistent headache and no headache was significant (p=0.001) and remained so after additional adjusting for headache on the experimental day.

Mechanical pain thresholds

Pressure pain thresholds by headache frequency

In individuals with neck pain, temporal PPT was lower in chronic headache, 178.1 ± 67.6 compared to episodic headache, 223.6 ± 97.6 and to the no headache group, 244.8 ± 109.5 (Figure 1b). None of the groupwise comparisons were significant after adjusting for age and sex, and additional adjustment for coexistent headache.

In individuals without neck pain, temporal PPT was lower in chronic headache, 180.7 ± 49.9 compared to episodic headache, 240.0 ± 104.0 and no headache group, 254.9 ± 102.3 (Figure 1b). None of the groupwise comparisons were significant after adjusting for age and sex, and additional adjustment for coexistent headache.

In individuals with neck pain, mean finger PPT was lower in chronic headache, 242.2 ± 111.0, and in episodic headache, 290.1 ± 150.3, compared to no headache group, 299.4 ± 140.4 (Figure 1c). None of the groupwise comparisons were significant after adjusting for age and sex, and additional adjustment for coexistent headache.

In individuals without neck pain, mean finger PPT was higher in chronic headache, 317.1 ± 113.2 compared to episodic headache, 307.2 ± 125.3 and no headache group, 315.8 ± 141.0 (Figure 1c). None of the groupwise comparisons were significant after adjusting for age and sex, and additional adjustment for coexistent headache.

Pressure pain thresholds by headache type

In individuals with neck pain, mean temporal PPT was lower in coexistent headache 209.4 ± 94.8 and TTH, 217.4 ± 92.4 compared to migraine, 234.1 ± 103.4 and no headache, 244.8 ± 109.5 (overall p=0.46, adjusted for age and sex), (Table 2). None of the age- and sex-adjusted groupwise comparisons were significant.

In individuals without neck pain, mean temporal PPT was lower in coexistent headache, 192.4 ± 73.5 and TTH, 223.0 ± 89.2 compared to migraine, 251.9 ± 116.0 and no headache 254.9 ± 102.3 (overall p=0.77, adjusted for age and sex), (Table 2). None of the age- and sex-adjusted groupwise comparisons were significant.

In individuals with neck pain, mean finger PPT was 274.9 ± 137.5 in individuals with coexistent headache, 272.7 ± 135.4 in individuals TTH, 329.2 ± 182.9 in individuals with migraine and 299.4 ± 140.4 in individual with no headache (overall p=0.15, adjusted for age and sex), (Table 2). None of the age- and sex-adjusted groupwise comparisons were significant.

In individuals without neck pain, mean finger PPT was lower in coexistent headache, 273.5 ± 91.2 and migraine, 304.0 ± 116.5, compared to TTH, 348.5 ± 146.2 and no headache 315.8 ± 141.0 (overall p=0.42, adjusted for age and sex), (Table 2). None of the age- and sex-adjusted groupwise comparisons were significant.

Stimulus response functions for pressure pain

Temporal muscle

In individuals with neck pain, mean AUC for the stimulus response function for the temporal muscle was 767.1 ± 1,081.3 in individuals with no headache, 1,121.0 ± 1,374.9 in individuals with episodic headache and 3,160.4 ± 2,520.6 in individuals with chronic headache (overall p<0.001, adjusted for age and sex), (Figure 2b). The age- and sex-adjusted difference was significant between chronic headache and episodic headache (p<0.001) and chronic headache and no headache (p<0.001) and remained so after additional adjusting for headache on the examination day, but the difference between episodic headache and no headache was not significant. After adjustment with age, sex, coexistent headache, mean AUC for the stimulus response function for the temporal muscle was only significantly higher in chronic headache compared to episodic headache and no headache groups (p<0.001 and p=0.01 respectively), and between chronic and episodic headache groups (p<0.001).

Figure 2: (a) and (b) Stimulus–response functions for pressure vs. pain in the temporalis muscle according to headache frequency without (a) and with (b) coexistent neck pain in the past year (mean VAS-score ± SEM). Generalized Linear Models (GLM) analysis controlling for the effect of covariates: age (<50; ≥50 years), sex. Pairwise comparisons with Bonferroni correction were performed to compare outcome variables between groups. SEM, standard error of mean; NS: p>0.05, *: p≤0.05, **: p≤0.01, ***: p≤0.001. Only p values for significant pairwise comparisons are shown.
Figure 2:

(a) and (b) Stimulus–response functions for pressure vs. pain in the temporalis muscle according to headache frequency without (a) and with (b) coexistent neck pain in the past year (mean VAS-score ± SEM). Generalized Linear Models (GLM) analysis controlling for the effect of covariates: age (<50; ≥50 years), sex. Pairwise comparisons with Bonferroni correction were performed to compare outcome variables between groups. SEM, standard error of mean; NS: p>0.05, *: p≤0.05, **: p≤0.01, ***: p≤0.001. Only p values for significant pairwise comparisons are shown.

In individuals without neck pain, mean AUC for the stimulus response function in the temporal muscle was 542.0 ± 840.9 in individuals with no headache, 985.0 ± 1,219.5 in individuals with episodic headache and 1782 ± 354.5 in individuals with chronic headache (overall p=0.003, adjusted for age and sex), (Figure 2a). The age- and sex-adjusted difference was significant between chronic headache and no headache (p=0.006) and remained so after additional adjusting for headache on the experimental day, but the difference between chronic and episodic headache was not significant. None of the groupwise comparisons adjusted for age, sex and coexistent headache were significant.

Trapezius muscle

In individuals with neck pain, mean AUC for the stimulus response function for the trapezius muscle was 1,548.7 ± 1,488.5 in individuals with no headache, 2,634.7 ± 2,243.0 in individuals with episodic headache and 4,393.8 ± 2,826.2 in individuals with chronic headache (overall p<0.001, adjusted for age and sex), (Figure 3b). The age- and sex-adjusted difference was significant between chronic headache and episodic headache (p<0.001), chronic headache and no headache (p<0.001) and episodic headache and no headache (p=0.003). The differences remained significant after additional adjusting for headache on the examination day. When adjusted for age sex, and coexistent headache, mean AUC for the stimulus response function for the trapezius muscle was only significant between chronic and episodic headache groups (p=0.004).

Figure 3: (a) and (b) Stimulus–response functions for pressure vs. pain in the trapezius muscle according to headache frequency without (a) and with (b) coexistent neck pain in the past year (mean VAS-score ± SEM). Generalized Linear Models (GLM) analysis controlling for the effect of covariates: age (<50; ≥50 years), sex. Pairwise comparisons with Bonferroni correction were performed to compare outcome variables between groups. SEM, standard error of mean; NS: p>0.05, *: p≤0.05, **: p≤0.01, ***: p≤0.001. Only p values for significant pairwise comparisons are shown.
Figure 3:

(a) and (b) Stimulus–response functions for pressure vs. pain in the trapezius muscle according to headache frequency without (a) and with (b) coexistent neck pain in the past year (mean VAS-score ± SEM). Generalized Linear Models (GLM) analysis controlling for the effect of covariates: age (<50; ≥50 years), sex. Pairwise comparisons with Bonferroni correction were performed to compare outcome variables between groups. SEM, standard error of mean; NS: p>0.05, *: p≤0.05, **: p≤0.01, ***: p≤0.001. Only p values for significant pairwise comparisons are shown.

In individuals without neck pain, mean AUC for the stimulus response function for the trapezius muscle was 1,254.7 ± 1,462.2 in individuals with no headache, 2,401.5 ± 2,357.0 in individuals with episodic headache and 2,500.0 ± 2,101.6 in individuals with chronic headache (overall p=0.049, adjusted for age and sex), (Figure 3a). None of the groupwise comparisons were significant after adjusting for age and sex, and additional adjustment for coexistent headache.

Correlations

There was a positive correlation between number of days with neck pain in the past year and TTS (r=0.457, p<0.001), number of days with neck pain in the past year and AUC for the temporal muscle (r=0.284, p<0.001) and number of days with neck pain in the past year and AUC for the trapezius muscle (r=0.366, p<0.001). There was a negative correlation between number of days with neck pain in the past year and temporal PPT (r=−0.14, p=0.002) and number of days with neck pain in the past year and finger PPT (r=−0.095, p=0.035).

Discussion

We found that TTS was highest in individuals with chronic headache, intermediate in those with episodic headache and lowest in control participants; differences were more pronounced in individuals with coexistent neck pain. Similarly, we found that frequency of coexistent neck pain positively correlated with TTS. When considering the type of headache, individuals with neck pain and coexistent headache followed by individuals with TTH, and then migraine had higher TTS compared to controls. Temporalis and trapezius SR-functions results also support that tenderness is increased in individuals with coexistent neck pain and chronic headache to higher degree than in those with episodic headache and more so in those without coexistent neck pain. Temporal PPTs were also numerically but not significantly lower in individuals with chronic headache followed by those with episodic headache than in controls, independent of coexisting neck pain. We noted a negative correlation between number of days with neck pain in the past year and temporal PPT and to a lesser degree for finger PPT; these findings indicate that frequent coexistent neck pain is associated with greater pain sensitivity.

The influence of coexistent neck pain on pain sensitivity in primary headaches such as TTH and migraine has not been studied extensively. To our knowledge there are no comparative studies on pain sensitivity in patients with TTH with and without coexistent neck pain. One small study with patients with low-frequency episodic migraine with and without coexistent neck pain (neck pain between the migraine attacks) from tertiary headache center [32] assessed pericranial tenderness and mechanical pain thresholds in the forehead (V1 dermatomal distribution) and the posterior neck (C2, C3 dermatomal distribution). Patients with episodic migraine with coexistent neck pain (neck pain between the migraine attacks) were found to have higher neck and cephalic tenderness scores, compared to migraine patients those without neck pain. No control subjects were included in this study. In the same study [32], both cephalic and neck mechanical pain thresholds of patients with episodic migraine and with coexistent neck pain were lower than those without neck pain but the difference was not statistically significant. Based on these results, the authors suggested that the peripheral mechanism may play an important role in the presence of neck pain in the patients with episodic migraine. Pericranial tenderness is common feature of migraine and TTH and can be more pronounced in individuals with chronic TTH [27, 33], [34], [35], [36]. Our findings of pronounced pericranial myofascial tenderness in individuals with chronic followed by episodic headache compared to controls and more so in those with coexistent neck pain suggest that coexistent neck pain may potentially be involved in peripheral sensitization in patients with TTH and migraine. However, involvement of the posterior neck could also suggest sensitization of upper cervical primary afferents or of the second order neuron in the trigeminocervical complex, i.e., central sensitization [37]. In our study coexistent neck pain was also found to be associated with lower cephalic and to some degree lower extracephalic PPTs in chronic headache subgroup compared to episodic headache and control subgroups. These findings suggest that comorbidity of neck pain and frequent headaches is associated with signs of central sensitization. It has been debated whether central sensitization facilitates the onset of neck pain in patients with TTH and migraine or vice versa or might be the consequence of comorbidity. However, a 12-year longitudinal follow-up study [38] previously demonstrated that patients who developed episodic TTH had increased pericranial myofascial tenderness but normal general pain sensitivity at follow-up, whereas subjects who developed chronic TTH had normal pain sensitivity at baseline but developed increased central pain sensitivity at follow-up. This strongly indicates that increased pain sensitivity in chronic headache is a consequence of frequent episodic headache, not a risk factor, and that central sensitization plays an important role for the chronification of headache. It is most likely, that neck pain can contribute to central sensitization in a similar way.

Coexistent pain conditions may alter pain sensitivity in individuals with TTH and migraine. We have previously demonstrated that in individuals with TTH and migraine, the presence of back pain was associated with increased central sensitization and peripheral sensitivity such as pericranial muscular tenderness compared with individuals without headache [39]. The pathophysiological mechanisms involving coexistent neck pain and subsequent pronounced pericranial tissues and muscle tenderness in individuals with TTH and migraine may differ from similar symptoms developed during or after headache attacks in both diseases.

In one questionnaire-based study [40] a total of 69% of migraine patients reported neck pain during a migraine headache phase. Moreover, in the same study [40] 54% of individuals with migraine reported neck pain with the start of the headache phase, and in 24% neck pain was reported within 2 h before the aura in patients with migraine with aura and before the onset of headache phase in those with migraine without aura. In a tertiary clinic study [8], up to 1/3 of all migraine attacks were reported to begin with tenderness of neck and shoulder muscles that gradually developed into a low-grade occipital headache. Neck symptoms are reported by 30% of patients with migraine before the migraine pain starts [41]. It is possible neck pain and muscle tenderness that begin at the onset of migraine may differ from neck muscle tenderness that appear after onset of migraine. It has previously been suggested that migraine localized to occipital region in particular may be generated in trigemino-cervical complex central neurons which receive nociceptive input from the pericranial muscles, skin overlying the back of the head and intracranial dura mater [22, 42, 43]. However, the muscle spasms or tension of scalp, neck and shoulder muscles may also sensitize peripheral nociceptor and induce headache [44, 45]. More evidence suggests that pericranial tenderness is not only a consequence of migraine but may play a role in the development of migraine, especially so in the chronification and with coexistent TTH. It has been reported that injection of hypertonic saline in splenius capitis, sternocleidomastoid and trapezius muscles of healthy subjects produced the pain in the occipital and posterior neck regions as well as referred pain in trigeminal nerve distribution, mimicking the clinical presentation of primary headaches [46]. Animal studies have demonstrated that sensory fibers from intracranial meningeal nociceptors can cross the calvarial bones through the sutures and reach pericranial muscles [47, 48]. A more recent study [49] has shown that activation of posterior dural nociceptors intracranially can result in headache and muscle tenderness/pain by activation of branches of the same nerve rather than convergence of dural and muscle afferents on trigemino-cervical complex. In contrast, the central sensitization may be responsible for neck muscle tenderness that develops after the onset of migraine attack [50, 51].

Increased pericranial tenderness in individuals with TTH and migraine with coexistent neck pain in our study could potentially be due to sustained muscle contraction and increased release of inflammatory mediators in the muscles. Active myofascial trigger points were shown to be more frequent in patients presenting with mechanical neck pain, migraine and TTH, than in healthy subjects [52, 53]. Neck pain and dysfunctions in neck muscles have been suggested to be a trigger of both TTH and migraine [54], [55], [56], [57], [58]. In women with CTTH, a greater co-activation of antagonist musculature during cervical extension and flexion contractions compared with healthy women was reported [56]. It has been suggested that increased co-activation of antagonist musculature may be due to reorganization of the motor control strategy in patients with CTTH which may potentially lead to muscle overload and increased nociception [56].

Methodological strengths and limitations in the current study sample have previously been reported [1, 39]. These include a relatively high response rate with representative individuals who participated in the headache interview (65.2%) and pain perception assessment/examination (62.2%), whereas the reports are retrospective and headache diaries were not used [1, 59]. Moreover, we could not identify participants with chronic migraine in our analysis due to the headache questionnaires used in the study, but they may have been included in a subset of the patients with chronic headache. It needs to be noted that recall based measures and daily diary measures have been validated for up to 3 months, but to the best of our knowledge, not for a full year [60]. Another limitation of our study is that PPTs were only assessed in temporal muscle in the cranio-cervical region. Assessment of PPTs in cervical musculature including the levator scapulae, anterior scalene and suboccipital muscles in episodic migraine may be of high relevance when evaluating the neck pain’s role in primary headaches [61, 62]. Finally, by the cross-sectional nature of our study, we cannot assess whether the coexistent neck pain is the cause or trigger of increased pain sensitivity or consequence of headache due to peripheral or central sensitization. Therefore, a prospective and longitudinal study would be needed to answer these questions. The major advantage of the current study is a large population-based sample and well-characterized individuals with migraine and TTH, and subdivisions into episodic or chronic forms based on the interview conducted by a physician blinded for the initial diagnosis of primary headache disorder.

In conclusion, coexistent neck pain in individuals with migraine and TTH is associated with greater pericranial tenderness and pain sensitivity, particularly in those with chronic headache and to a lesser degree in those with episodic headache. As pericranial tenderness and pain sensitivity may index allodynia; these findings suggest that neck pain may be associated with peripheral sensitization or central sensitization in individuals with chronic headache. It is unclear if coexistent neck pain is a cause or consequence of sensitization. The findings of our study may have clinical implications. Recently, it was demonstrated that patients with migraine and co-existing TTH and neck pain had lower level of physical activity and psychological well-being, higher level of perceived stress and poorer self-rated health compared to healthy controls [63]. In a randomized controlled study with patients with migraine [64], aerobic exercise significantly improved the burden of migraine and the ability to engage in physical activity due to reduced impact of coexistent TTH and neck pain but the effect could not be explained by pain modulation [65]. Future studies should explore the interaction of coexistent neck pain with pharmacological and non-pharmacological interventions for migraine and TTH.

Corresponding author: Sait Ashina, MD, BIDMC Comprehensive Headache Center, Harvard Medical School, Boston, MA, USA; Department of Neurology, Critical Care and Pain Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA; Department of Anesthesia, Critical Care and Pain Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA02215, USA; and Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark, Phone: 617-278-8000, Fax: 617-754-8634, E-mail:

Acknowledgments

We thank Nurse Vibeke Thomsen for skillful assistance in conducting the clinical examination. We thank Ann C Lyngberg for conducting headache interviews.

  1. Research funding: The study was supported by grants from the East Denmark Health Science Research Forum, the Danish Medical Association Research Fund, the Danish Health Insurance Foundation, the Danish Hospital Foundation for Medical Research, the Danish Headache Society, the Cool Sorption Foundation, GlaxoSmithKline A/S, Merck Sharp Dohme A/S, Pfizer A/S, Lundbeck Pharma A/S and H. Lundbeck A/S. The funding sources have not been involved in the conduct of the study.

  2. Author contribution: Sait Ashina, Lars Bendtsen, Rami Burstein, Afrim Iljazi, Rigmor Hoejland Jensen, Richard B Lipton contributed to the design of the article, analysis and interpretation of data, drafting the article or revising it critically for important intellectual content, and writing of the article. All authors approved the final version of the article.

  3. Competing interests: Sait Ashina (S.A.) received honoraria for consulting from Allergan/AbbVie, Amgen, Biohaven, Eli Lilly, Impel NeuroPharma, Novartis, Satsuma, Supernus, Theranica, Percept. S.A. is an associate editor for Neurology Reviews and BMC Neurology, review editor for Frontiers in Neurology, serves on Advisory Board for Journal of Headache and Pain, and is the member of Education Committee if the of the International Headache Society. Lars Bendtsen (L.B.) has served on the scientific advisory board for Novartis, Allergan, Teva, Lundbeck and Eli Lilly. Rami Burstein (R.B.) is the John Hedley-Whyte Professor of Anesthesia and Neuroscience at the Beth Israel Deaconess Medical Center and Harvard Medical School. He has received research support from the NIH: R01 NS094198-01A1, R37 NS079678, R01NS095655, R01 NS104296, R21 NS106345, Allergan/Abbvie, Teva, Dr. Ready, Eli Lilly, Trigemina and the Migraine Research Foundation. He is a reviewer for NINDS, holds stock options in AllayLamp, Theranica and Percept; serves as consultant, advisory board member, or has received honoraria from: Alder, Allergan, Amgen, Autonomic Technologies, Avanir, Biohaven, Dr. Reddy’s Laboratory, electroCore, Eli Lilly, GlaxoSmithKline, Merck, Pernix, Theranica, Teva, and Trigemina. CME fees from Healthlogix, Medlogix, WebMD/Medscape. Rigmor Hoejland Jensen (R.H.J.) has received honoraria for lectures and patient leaflets from MSD, Berlin-Chemie Menarini, ATI, Novartis, Teva, Allergan and Pfizer and is conducting clinical trials for Eli-Lilly and Lundbeck. Richard B Lipton (R.B.L.) is the Edwin S. Lowe Professor of Neurology at the Albert Einstein College of Medicine in New York. He receives research support from the NIH and FDA. R.B.L. also receives support from the National Headache Foundation and the Marx Foundation. R.B.L. serves on the editorial board of Neurology, senior advisor to Headache, and associate editor to Cephalalgia and has reviewed for the NIA and NINDS, holds stock options in Biohaven Holdings, Manistee and CntrlM; serves as consultant, advisory board member, or has received honoraria or conducted research funded by Allergan/Abbvie, American Academy of Neurology, American Headache Society, Amgen, Biohaven, Dr. Reddy’s (Promius), Electrocore, Eli Lilly, GlaxoSmithKline, Grifols, Lundbeck, Pernix, Pfizer, Teva, Trigemina, Vector, Vedanta. R.L. receives royalties from Wolff’s Headache 7th and 8th Edition, Oxford Press University, 2009, Wiley and Informa. All other authors declare no competing interests.

  4. Informed consent: Informed consent has been obtained from all individuals included in this study.

  5. Ethical approval: Research involving human subjects complied with all relevant national regulations, institutional policies and is in accordance with the tenets of the Helsinki Declaration (as amended in 2013), and the study has been approved by the Ethical Committee for Copenhagen County and by the Danish Data Protection Agency (protocol number for cross-sectional study: KA 00174).

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Received: 2022-02-07
Revised: 2022-05-14
Accepted: 2022-06-30
Published Online: 2022-09-26
Published in Print: 2023-01-27

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Editorial Comment
  3. What do we mean by “mechanism” in pain medicine?
  4. Topical Reviews
  5. Topical review – salivary biomarkers in chronic muscle pain
  6. Tendon pain – what are the mechanisms behind it?
  7. Systematic Review
  8. Psychological management of patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS): a systematic review
  9. Topical Review
  10. Predicting pain after standard pain therapy for knee osteoarthritis – the first steps towards personalized mechanistic-based pain medicine in osteoarthritis
  11. Clinical Pain Researches
  12. Neuropathy and pain after breast cancer treatment: a prospective observational study
  13. Neuropeptide Y and measures of stress in a longitudinal study of women with the fibromyalgia syndrome
  14. Nociceptive two-point discrimination acuity and body representation failure in polyneuropathy
  15. Pain sensitivity in relation to frequency of migraine and tension-type headache with or without coexistent neck pain: an exploratory secondary analysis of the population study
  16. Clinician experience of metaphor in chronic pain communication
  17. Observational studies
  18. Chronic vulvar pain in gynecological outpatients
  19. Male pelvic pain: the role of psychological factors and sexual dysfunction in a young sample
  20. A bidirectional study of the association between insomnia, high-sensitivity C-reactive protein, and comorbid low back pain and lower limb pain
  21. Burden of disease and management of osteoarthritis and chronic low back pain: healthcare utilization and sick leave in Sweden, Norway, Finland and Denmark (BISCUITS): study design and patient characteristics of a real world data study
  22. Factors influencing quality of life in patients with osteoarthritis: analyses from the BISCUITS study
  23. Prescription patterns and predictors of unmet pain relief in patients with difficult-to-treat osteoarthritis in the Nordics: analyses from the BISCUITS study
  24. Lifestyle factors, mental health, and incident and persistent intrusive pain among ageing adults in South Africa
  25. Inequalities and inequities in the types of chronic pain services available in areas of differing deprivation across England
  26. Original Experimentals
  27. Conditioned pain modulation is not associated with thermal pain illusion
  28. Association between systemic inflammation and experimental pain sensitivity in subjects with pain and painless neuropathy after traumatic nerve injuries
  29. Endometriosis diagnosis buffers reciprocal effects of emotional distress on pain experience
  30. Educational Case Reports
  31. Intermediate cervical plexus block in the management of treatment resistant chronic cluster headache following whiplash trauma in three patients: a case series
  32. Trigeminal neuralgia in patients with cerebellopontine angle tumors: should we always blame the tumor? A case report and review of literature
  33. Short Communication
  34. Less is more: reliability and measurement error for three versions of the Tampa Scale of Kinesiophobia (TSK-11, TSK-13, and TSK-17) in patients with high-impact chronic pain
https://doi.org/10.1515/sjpain-2022-0030
Keywords for this article
central sensitization; comorbidity; headache; neck pain; pain threshold; peripheral sensitization; population; tenderness

Articles in the same Issue

  1. Frontmatter
  2. Editorial Comment
  3. What do we mean by “mechanism” in pain medicine?
  4. Topical Reviews
  5. Topical review – salivary biomarkers in chronic muscle pain
  6. Tendon pain – what are the mechanisms behind it?
  7. Systematic Review
  8. Psychological management of patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS): a systematic review
  9. Topical Review
  10. Predicting pain after standard pain therapy for knee osteoarthritis – the first steps towards personalized mechanistic-based pain medicine in osteoarthritis
  11. Clinical Pain Researches
  12. Neuropathy and pain after breast cancer treatment: a prospective observational study
  13. Neuropeptide Y and measures of stress in a longitudinal study of women with the fibromyalgia syndrome
  14. Nociceptive two-point discrimination acuity and body representation failure in polyneuropathy
  15. Pain sensitivity in relation to frequency of migraine and tension-type headache with or without coexistent neck pain: an exploratory secondary analysis of the population study
  16. Clinician experience of metaphor in chronic pain communication
  17. Observational studies
  18. Chronic vulvar pain in gynecological outpatients
  19. Male pelvic pain: the role of psychological factors and sexual dysfunction in a young sample
  20. A bidirectional study of the association between insomnia, high-sensitivity C-reactive protein, and comorbid low back pain and lower limb pain
  21. Burden of disease and management of osteoarthritis and chronic low back pain: healthcare utilization and sick leave in Sweden, Norway, Finland and Denmark (BISCUITS): study design and patient characteristics of a real world data study
  22. Factors influencing quality of life in patients with osteoarthritis: analyses from the BISCUITS study
  23. Prescription patterns and predictors of unmet pain relief in patients with difficult-to-treat osteoarthritis in the Nordics: analyses from the BISCUITS study
  24. Lifestyle factors, mental health, and incident and persistent intrusive pain among ageing adults in South Africa
  25. Inequalities and inequities in the types of chronic pain services available in areas of differing deprivation across England
  26. Original Experimentals
  27. Conditioned pain modulation is not associated with thermal pain illusion
  28. Association between systemic inflammation and experimental pain sensitivity in subjects with pain and painless neuropathy after traumatic nerve injuries
  29. Endometriosis diagnosis buffers reciprocal effects of emotional distress on pain experience
  30. Educational Case Reports
  31. Intermediate cervical plexus block in the management of treatment resistant chronic cluster headache following whiplash trauma in three patients: a case series
  32. Trigeminal neuralgia in patients with cerebellopontine angle tumors: should we always blame the tumor? A case report and review of literature
  33. Short Communication
  34. Less is more: reliability and measurement error for three versions of the Tampa Scale of Kinesiophobia (TSK-11, TSK-13, and TSK-17) in patients with high-impact chronic pain
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