Abstract
Introduction: The aim was to investigate bilateral, wide-spread pressure pain hyperalgesia in symptomatic (trigeminocervical) and non-symptomatic (pain-free distant) regions in children with frequent episodic tension-type headache (FETTH).
Methods: Twenty-five children, 6 boys and 19 girls (mean age, 8.9 ± 1.8 years) with FETTH and 50 age- and sex-matched healthy children (12 boys, 38 girls; mean age: 8.8 ± 1.7 years) were recruited. Pressure pain thresholds (PPTs) were bilaterally assessed over temporalis muscle, upper trapezius muscle, second metacarpal and tibialis anterior muscles in a blinded design.
Results: The results showed that PPT levels were significantly decreased bilaterally over the temporalis, upper trapezius and tibialis muscles, and the second metacarpal in children with FETTH as compared to controls (all sites, P < 0.001). No significant differences in the magnitude of PPT decrease between the upper trapezius muscle, second metacarpal and tibialis anterior muscles were found. PPT over both upper trapezius muscles were negatively correlated with the history and intensity of headache (rs = −0.415; P = 0.045).
Conclusions: The findings revealed bilateral, wide-spread pressure pain hypersensitivity in children with FETTH suggesting that wide-spread central sensitisation is involved in children with this headache pain condition.
Introduction
Tension-type headache may cause substantial levels of disability for patients and their families as well as to the global society due to very high prevalence in the general population (1,2). Tension-type headache shows a reported 1-year prevalence rate of 38.3% for the episodic form and 2.2% for the chronic form (3). In addition, the prevalence of this particular headache has increased over the years (4). In a recent epidemiological study in Germany, the 6-month prevalence of headaches was 53.2% among children aged 7–14 years (5). Lewis et al. (6) estimated that about 20% of the children with primary headache need medical therapy.
Although there has been an increasing interest in the pathogenic mechanisms of tension-type headache, the true patho-anatomical mechanisms remain unclear (7). It seems clear that hyperexcitability of peripheral and central nociceptive pain pathways plays an important role in this condition (8). These sensitisation mechanisms result in increased muscle tenderness (9) and pressure pain hyperalgesia, particularly in adults with chronic tension-type headaches (10–12). Nevertheless, few studies have focused on children with tension-type headache. Anttila et al. (13) reported that children with migraine, but not with tension-type headache, showed increased muscle tenderness at palpation of the pericranial, neck and shoulder muscles. In a later study, the same authors found that neither children with migraine nor episodic tension-type headache show increased extracephalic muscular sensitivity to palpation (14). However, these authors recognised that the lack of increased muscle tenderness in tension-type headache could be related to the fact that most of the children had quite infrequent headache episodes. Therefore, the results from these studies can not be extrapolated to frequent episodic or chronic tension-type headaches. In fact, Tüzun et al. (15) reported pressure pain hyperalgesia (lower pressure pain threshold levels) in the upper trapezius muscle in adolescents with chronic tension type headache as compared to healthy children.
A recent study demonstrated that adults with chronic tension-type headache had wide-spread pressure pain hypersensitivity suggesting that pain processing in the central nervous system is abnormal in this pain disorder (16). To the best of the authors’ knowledge, no previous study has investigated wide-spread pressure hypersensitivity in children with tension-type headache. In order to investigate central nociceptive processing gain in children with tension-type headache, the aim of this study was to analyse the presence of wide-spread pressure hyperalgesia in symptomatic (trigeminocervical) and non-symptomatic (distant pain-free) regions in children with episodic tension-type headache.
Subjects and methods
Study design
A case-control study was designed with two controls selected for each case.
Subjects
Consecutive children diagnosed with tension-type headache by an experienced neuropaediatrist from the Neurology Department of Hospital Quirón were screened for eligibility criteria. In all children, headache features, temporal profile and family history were assessed from the clinical history. To be included, children had to describe all the characteristics typical of frequent episodic tension-type headache (FETTH) following the common criteria of the International Headache Society (17): bilateral location, pressing or tightening pain, mild/moderate intensity (≤6 on a numerical pain rate scale) and no aggravation of headache during physical activity. Only one, either photophobia or phonophobia, was permitted. No children reported vomiting or evident nausea during pain attacks. Other primary headaches were excluded. Each child fulfilled the criteria for FETTH and no apparent evidence of secondary headaches was present. Medication-overuse headache according to the International Headache Society criteria was excluded (17). Children with diagnosis of depression were also excluded. No children were taking any prophylactic drug. Additionally, age- and sex-matched children without history of head or neck pain symptoms were recruited from volunteers who responded to a local announcement. Ethical approval was granted by the local ethics committee (FHA 043). Informed consent was obtained from both children and parents and all procedures were conducted according to the Declaration of Helsinki.
Self-reported measures
Children completed a headache diary for 4 weeks in order to complement the diagnosis (18). An 11-point numerical pain rate scale (19) (NPRS; range, 0 = no pain to 10 = maximum pain) was used to assess headache intensity. The headache diary was used to calculate the following variables: (i) headache intensity, calculated from the mean of the NPRS of the days with headache; (ii) headache frequency, calculated by dividing the number of days with headache by the number of the analyzed weeks (days/week); and (iii) headache duration, calculated by dividing the sum of the total hours of headache by the number of days with headache (h/day).
The Beck Depression Inventory (BDI-II), a 21-item self-report measure assessing affective, cognitive and somatic symptoms of depression, was also used (20). Children, with the help of parents, were asked to choose from a group of sentences which best described how they had been feeling in the preceding 2 weeks. For example, to assess sadness, they could choose between ‘I do not feel sad’, ‘I feel sad much of the time’, ‘I am sad all the time’, or ‘I am so sad or unhappy that I can not stand it’. The BDI-II has shown good internal consistency (α = 0.86) with higher scores indicating higher levels of depressive symptoms (21,22).
Pressure pain threshold assessment
Pressure pain threshold (PPT) is defined as the minimal amount of pressure where a sensation of pressure first changes to pain (23). An electronic algometer (Somedic AB, Farsta, Sweden) was used to measure PPT (kPa). The pressure was applied at a rate of 30 kPa/s. All participants were instructed to press a switch when the sensation changed from pressure to pain. The mean of three trials (intra-examiner reliability) was calculated and used for the main analysis. A 30-s resting period was allowed between each measure. The reliability of pressure algometry has been found to be high (ICC = 0.91 [95% CI 0.82–0.97]) (24).
Children attended a preliminary session for familiarisation with the pressure test procedures. Children were examined on days that were headache-free. PPT levels were measured bilaterally over temporalis muscle, upper trapezius muscle, second metacarpal, and the tibialis anterior muscle by an assessor blinded to the children’s condition. The order of assessment was randomised on each participant.
Sample size determination
The sample size determination and power calculations were performed with appropriate software (Tamaño de la Muestra1.1©, Spain). The calculations were based on detecting, minimally, significant clinically differences of 20% on PPT levels between both groups (25) with an alpha level of 0.05, a desired power of 80% and an estimated inter-individual coefficient of variation for PPT measures of 20%. This generated a sample size of at least 16 participants per group.
Pressure pain threshold data management
In the current study, the magnitude of sensitisation was investigated assessing the differences of absolute and relative PPT values between both groups. For relative values, we calculated a ‘PPT index’, dividing PPT of each subject at each point by the mean of the PPT score of the control group at the same point. A PPT index <100% indicate pressure pain sensitisation.
Statistical analysis
Data were analysed with the SPSS statistical package (v.14.0). Results are expressed as mean and 95% confidence interval (95% CI). The Kolmogorov–Smirnov test was used to analyse the normal distribution of the variables (P > 0.05). Quantitative data without a normal distribution (i.e. pain history, headache intensity, frequency or duration) were analysed with non-parametric tests, and data with a normal distribution (PPTs) were analysed with parametric tests. The intraclass correlation coefficient (ICC) was used to assess intra-examiner reliability of PPT data. A two-way ANOVA test was used to investigate the differences in PPT assessed over each point (temporalis muscle, upper trapezius muscle, second metacarpal, tibialis anterior muscle) with side (dominant or non-dominant) as within-subject factor and group (CTTH, controls) as the between-subject factor. A two-way ANOVA test was also used for assessing differences in PPT Index with side (dominant/non-dominant) as within-patient factor and point (temporalis muscle, upper trapezius muscle, second metacarpal, tibialis anterior) as between-patient factor. Post-hoc comparisons were done with the Tukey test. Finally, the Spearman’s rho (rs) test was used to analyse the association between PPTs and the clinical variables relating to symptoms. The statistical analysis was conducted at a 95% confidence level and a P-value less than 0.05 was considered statistically significant.
Results
Demographic and clinical data of the sample
Fifty consecutive children presenting with headache between May and December 2009 were screened for possible eligibility criteria. Twenty-five children were excluded: migraine (n = 8), hemicranial headache (n = 7), higher levels of depression (BDI-II > 15; n = 10). Finally, a total of 25 children, 6 boys and 19 girls, aged 5–11 years (mean, 8.9 ± 1.8 years) satisfied all the inclusion criteria and agreed to participate. In our sample, headache history was 1.9 years (95% CI 1.5–2.2 years), mean headache period per day was 4.3 h (95% CI 3.3–5.2 h), the mean intensity per episode was 5.2 (95% CI 4.8–5.6), and the number of days per month with headache was 12.7 (95% CI 10.2–14.5 days per month). No significant association between the headache parameters (intensity, frequency or duration) was found (P > 0.7). Finally, the BDI-II score was 3.5 (95% CI 3.0–4.1). In fact, a significant positive relation (rs = 0.525; P = 0.07) between BDI-II score and headache frequency was found: the greater the frequency of headache attacks, the greater the score of BDI-II.
In addition, 50 age- and sex-matched children without headache, 12 boys and 38 girls, aged 5–11 years (mean: 8.8 ± 1.7 years) also participated (P = 0.874).
Pressure pain sensitivity over trigeminocervical symptomatic areas
The intra-examiner repeatability of PPT readings over the temporalis and upper trapezius muscles was 0.91 and 0.93, respectively, for both sides. The SEM was 5.1 kPa and 5.8 kPa, respectively, for both sides.
Differences in pressure pain thresholds (kPa) over the temporalis, upper trapezius and tibialis anterior muscles and over the second metacarpal between children with tension-type headache and healthy controls
Values are expressed as mean ± SD (95% confidence interval).
Significant differences between patients and controls (two-way ANOVA test).
Pressure pain sensitivity over extratrigeminal distant pain-free areas
The intra-examiner repeatability of PPT readings over the second metacarpal and tibialis anterior muscle was 0.90 and 0.93, respectively, for both sides. The SEM was 6.2 kPa and 6.7 kPa, respectively, for both sides.
The ANOVA revealed significant differences between both groups, but not between sides, for PPT levels over the second metacarpal (group, F = 427.4; P < 0.001; side, F = 1.6; P = 0.294) and the tibialis anterior muscle (group, F = 529.8; P < 0.001; side, F = 0.8; P = 0.773). Again, children with FETTH showed bilateral lower PPT levels in both points than controls (P < 0.001). Table 1 details PPT levels over the second metacarpal and tibialis anterior muscle for both sides within each group.
Pressure pain threshold indices
The ANOVA showed significant differences for PPT indices between sites (F = 6.6; P < 0.001) and sides (F = 4.6; P = 0.033), but not a side × time interaction (F = 1.1; P = 0.325). Post-hoc analysis revealed that PPT index in the temporalis muscle was less impaired as compared to PPT indices in the upper trapezius muscle (P = 0.045), second metacarpal (P < 0.001) and tibialis anterior muscle (P = 0.02). Further, PPT indices in the dominant side were slightly more impaired than the indices within the non-dominant side (P > 0.05; Fig. 1).
Pressure pain threshold indices in upper trapezius, temporalis, second metacarpal and tibialis anterior muscle. The boxes represent the mean and percentile scores and the error bars represent the standard deviation.
Pressure sensitivity and clinical features in children with tension-type headache
Significant negative correlation between years of headache and PPT over the upper trapezius muscles (both sides, rs = −0.415; P = 0.045) was found: the longer the years with headache, the lower the PPT levels. Further, the intensity of headache was also negatively correlated with bilateral PPT levels over upper trapezius muscles (both sides, rs = −0.41; P = 0.045). In such way, the greater the pain intensity, the lower the bilateral PPT levels. Finally, a negative correlation (rs = −0.47; P = 0.02) between the intensity of the headache and PPT levels over the dominant tibialis anterior muscle was also found: the greater the intensity of the headache, the lower the PPT levels over the dominant tibialis anterior muscle.
Discussion
The main finding of the present study was a bilateral and wide-spread pressure hypersensitivity in children with frequent episodic tension-type headache (FETTH) as compared to healthy children, suggesting that both peripheral and central sensitisation mechanisms may be involved.
Both peripheral and central sensitisation mechanisms have been found in several local pain syndromes: shoulder pain (26), chronic tension-type headache (27), repetitive strain injury (28), carpal tunnel syndrome (29), low back pain (30), lateral epicondylalgia (31), osteoarthritis (32), and myofascial temporomandibular disorders (33). All these studies have consistently showed lower PPT in both local painful and distant pain-free areas, suggesting that wide-spread pressure hyperalgesia reflects generalised hyperexcitability of the second-order (or higher) nociceptive neurons in the central nervous system. The current study is the first to provide evidence of wide-spread and multisegmental sensitisation in children with FETHH as we have found significant bilateral decreases in PPT over the second metacarpal and tibialis anterior muscle. Additionally, clinical evidence consistent with the theory that tension-type headache is associated with a hyperexcitability of the central nervous system is that fibromyalgia syndrome is usually co-morbid (34,35). We do not know if children with FETTH would be more susceptible to suffer from fibromyalgia in the future.
An interesting result of the current study was that the magnitude of PPT changes in FETHH children was similar in the upper trapezius muscle (60–63%), the second metacarpal (57–61%) and the tibialis anterior muscle (61–62%), suggesting that the sensitisation process is not only restricted to the trigeminal second order neurons, but also to extratrigeminal nociceptive neurons. These findings support the concept of a central amplification of nociceptive input in children with FETTH. It is interesting to note that children with FETTH show a similar degree of pain sensitisation as adults with chronic tension-type headache. This finding may be related to the fact that children in the current study showed almost 15 days of headache per month (3.5–3.8 days/week), which close to the chronic form. It would be interesting to investigate if children with less headache frequency also show this degree of sensitisation.
In addition to central sensitisation, our results may reflect a dysfunctional state of endogenous pain modulatory systems, which has been previously reported in adults with chronic tension-type headache (36,37). Recent studies also highlight the importance of risk genes for enhanced pain sensitivity; for example, polymorphisms in the gene coding for the cathecol-O-methyl-transferase (COMT) have been associated with headache (38,39).
The presence of central sensitisation or decreased descending inhibition does not exclude the role of peripheral sensitisation mechanisms. In fact, since central sensitisation is considered a dynamic condition influenced by multiple factors including peripheral nociceptive inputs (40), it may be possible that peripheral nociceptive barrage may contribute to this sensitisation process. The existence of sensitisation mechanisms in local pain syndromes suggests that sustained peripheral noxious inputs to the central nervous system play a role in the initiation and maintenance of central sensitization (41). This evidence is supported by animal models where unilateral localised musculoskeletal pain caused sensitisation of contralateral segments (42).
Finally, we should consider some points of the current study. First, we included a subgroup of children with FETTH, with high frequency of headaches, and without depression. It would be interesting to investigate if children with less frequency of head pain attacks show similar degree of sensitisation. Second, we included both girls and boys with FETTH. It is known that women have less efficient pain habituation, greater susceptibility to the development of temporal summation of chemical (43), mechanical (44), and therma (45) pain, and less efficient diffuse noxious inhibitory pathways (46,47) than males. Since we included 6 boys with FETTH, we cannot compare gender differences in pressure pain sensitivity. Future studies with greater sample sizes should compare whether bilateral wide-spread mechanical pain sensitivity and the degree of sensitisation is different between girls and boys.
Conclusions
We found a bilateral and wide-spread pressure hypersensitivity in children with frequent episodic tension-type headache as compared to healthy children, which suggests that peripheral and central sensitisation mechanisms may be involved. Future studies are needed to elucidate further the role of sensitisation mechanisms in children with FETTH.
Footnotes
Acknowledgements
This study received funds from a grant conceded by the Universidad Rey Juan Carlos and Comunidad de Madrid (reference CCG10-URJC/BIO-5011).