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. 2024 Nov 11;29(1):e4754. doi: 10.1002/ejp.4754

Exploring signs of central sensitization in adolescents with hypermobility Spectrum disorder or hypermobile Ehlers‐Danlos syndrome

Elke Schubert‐Hjalmarsson 1,2,✉, Anders Fasth 3,4, Kelly Ickmans 5,6,7, Ann‐Charlott Söderpalm 8, Mari Lundberg 5,9,10
PMCID: PMC11609890  PMID: 39529262

Abstract

Background

Hypermobility Spectrum Disorder (HSD) and Hypermobile Ehlers‐Danlos Syndrome (hEDS) are two overlapping heritable connective tissue disorders characterized by joint hypermobility, chronic pain, impaired body perception, and musculoskeletal symptoms. Central sensitization has been proposed as a plausible explanation for symptoms like widespread pain, fatigue, mood disorders, and sleep disturbances in patients with HSD/hEDS.

Objective

The aim of this study was to investigate signs of central sensitization, including exercise‐induced hypoalgesia (EIH), and fatigue severity in adolescents with HSD/hEDS.

Methods

In this prospective, experimental, case–control study, thirty‐seven adolescents with HSD/hEDS and 47 healthy adolescents (all aged 13–17 years) were included. Pressure pain thresholds (PPTs) were measured at four muscle groups using a pressure algometer. EIH was evaluated by measuring PPTs on two muscle groups immediately after an exercise test on a bicycle ergometer. Participants also completed questionnaires on fatigue and cognitive/emotional factors.

Results

The study demonstrated significantly lower PPTs in four different muscle groups in adolescents with HSD/hEDS compared to the healthy control group. Both groups achieved a significantly higher PPTs after exercise in the muscle involved in the activity. Adolescents with HSD/hEDS reported higher fatigue levels and more cognitive/emotional difficulties than the control group.

Conclusion

Adolescents with HSD/hEDS showed generalized hyperalgesia measured through PPTs at different body sites. EIH was partly affected in adolescents with HSD/hEDS, presenting as unchanged pain sensitivity in the remote muscle. Pain should be considered as a phenomenon that is influenced by different biopsychosocial factors, including possible central sensitization, which increase its complexity.

Significance statement

This study breaks new ground by showing signs of central sensitization, including diminished EIH, in adolescents with HSD or hEDS. Given that exercise is a key element in pain management, these findings offer valuable insights when developing treatment plans for adolescents with HSD or hEDS.

1. INTRODUCTION

Hypermobility Spectrum Disorder (HSD) and Hypermobile Ehlers‐Danlos Syndrome (hEDS) are two overlapping connective tissue disorders characterized by joint hypermobility, chronic pain, impaired body perception and other musculoskeletal problems (Castori et al., 2017; Malfait et al., 2017). The global prevalence of EDS is reported at 1:5000 (Pyeritz, 2000) but there are no specific paediatric data. A clear association between comorbidities such as fatigue, autonomic dysfunctions, gastrointestinal problems, and chronic pain in adolescents with HSD/hEDS has been demonstrated (Scheper, Nicholson, et al., 2017). Fatigue, defined as ‘an overwhelming sense of tiredness, lack of energy, and feeling of exhaustion, is not the same as muscle weakness’ (Voermans et al., 2010). Fatigue has been identified as a common and clinically significant problem in 86% of adults with EDS (Scheper et al., 2016; Voermans et al., 2010). Children and adolescents with HSD/hEDS participated less in social activities, and self‐report a lower health‐related quality of life as compared to healthy peers (Mu et al., 2019; Tran et al., 2020).

Intrusive pain is the main reason why adolescents with HSD/hEDS seek health care. Central sensitization has been proposed as a plausible explanation for clinical symptoms such as widespread pain, fatigue, mood disorders, and sleep disturbances found in patients with HSD/hEDS (Di Stefano et al., 2016; Rombaut et al., 2014). Signs of central sensitization in both adolescents and adults with HSD/hEDS have been described in previous studies (De Wandele et al., 2022; Scheper, Pacey, et al., 2017). It is hypothesized that central sensitization may be one of the main underlying mechanisms of nociplastic pain. (Nijs et al., 2023).

Dysfunctional pain inhibition after exercise may be a sign of central sensitization. In a healthy population, physical activity has an inhibitory effect on pain, also known as exercise‐induced hypoalgesia (EIH). EIH, described as an attenuation of pain following single episodes of exercise, is demonstrated by increased pain thresholds and/or tolerance levels, and decreased pain grading during and after exercise (Rice et al., 2019). This phenomenon is more evident after higher‐intensity exercise and when pain is assessed at the exercising body site (Naugle et al., 2012). In healthy individuals, a single training session can have a hypoalgesic effect. However, in individuals with chronic pain, this hypoalgesic effect may not occur (Naugle et al., 2012; Rice et al., 2019), instead manifesting as unchanged or increased sensitivity to pain after physical activity (Lima et al., 2017). There is a lack of knowledge as to whether EIH is impaired in adolescents with HSD/hEDS.

Chronic pain is often maintained or enhanced by cognitive and emotional factors, which can modulate activity in the descending nociceptive pathways (Nijs et al., 2012; Zusman, 2002). When investigating chronic pain in patients with HSD/hEDS, the recommendation is to also consider psychosocial factors that can influence a person's pain perception (Baeza‐Velasco et al., 2019).

In summary, the aims of this study were to explore signs of central sensitization including EIH and to examine fatigue severity in adolescents with HSD/hEDS.

2. METHODS

This prospective, experimental, case–control study compared adolescents with HSD/hEDS with healthy controls. The study protocol was registered at ClinicalTrials.gov PRS: Protocol Section NCT05633225 before data collection commenced.

2.1. Participants

This study was carried out from 1st of November 2022 to 31st of August 2023 and involved Swedish adolescents aged 13–17 years who had a clinical diagnosis of HSD/hEDS. The patients were identified via medical records at Children's Primary Health Care Clinics in Gothenburg and Southern Bohuslän, at Queen Silvia Children's Hospital, and Skaraborg Hospital, Sweden. Participants for the healthy control group were recruited through hospital staff and social media and matched for sex and age. Participants in both groups were excluded if they were: unable to read or understand Swedish, pregnant, or ≤1 year postpartum. Potential participants were excluded if they did not meet the 2017 diagnostic criteria for neither HSD nor hEDS (Castori et al., 2017; Malfait et al., 2017). Control group participants without history of medical health problems or regular use of medications must not have had pain lasting >24 h in the preceding 3 months or engage in elite‐level sports.

2.2. Procedures

Adolescents and their respective guardians in both groups received study information through letters and were invited to participate. Participants in the control group were informed about the requirement of being healthy and free of pain. Oral information sessions were offered to all participants and guardians. Participants under 15 years provided verbal assent, and those over 15 years and all guardians provided written consent before their assigned clinic appointment.

A single assessment session was conducted, with participants given the choice of two assessment locations, both standardized with identical equipment. Measurements were scheduled on Fridays or Saturdays, unless otherwise requested. Participants were instructed to refrain from moderate to vigorous physical exercise for 48 h prior to measurements, and asked to avoid consuming caffeine, alcohol, and nicotine on the measurement day. Ethically, nonopioid pain medication (COX‐inhibitors, paracetamol) was allowed for patients, but all participants were asked to abstain from analgesics for at least 24 h premeasurement.

Demographic data and pain scores were collected by the first assessor (physiotherapist) on the day of the assessment. This was followed by a medical examination by the second assessor (physician) using the 2017 HSD/hEDS diagnostic criteria (https://www.ehlers‐danlos.com/heds‐diagnostic‐checklist/) (Castori et al., 2017; Malfait et al., 2017). A third assessor (physiotherapist) instructed participants on measurement procedures and marked points for pressure pain threshold (PPT) tests that were repeated thrice at each site. Subsequently, participants completed a cycling test with self‐reported pain, experimental pain measures, and exhaustion recorded immediately post‐exercise. Finally, participants completed questionnaires. Assessors two and three were blinded to the participants' group affiliation. To avoid missing data, the questionnaires were checked immediately upon submission and could be completed on the spot.

2.3. Outcome measures

2.3.1. Joint hypermobility

The study defines joint hypermobility as exceeding normal range of motion in multiple joints (De Koning et al., 2023; Kirk et al., 1967). Assessment utilized the Beighton scale, a widely accepted tool examining: (1) dorsiflexion in the fifth metacarpophalangeal joint (>90°); (2) thumb opposition to the forearm; (3) elbow hyperextension (>10°); (4) knee hyperextension (>10°) and (5) ability to place hands‐flat‐on‐floor without bending the knees. Scores range up to nine, with one point per side for item 1–4 and one point for item 5. Joint hypermobility was categorized as peripheral, local, or generalized (Castori et al., 2017). Generalized hypermobility was defined as scoring six or higher on the Beighton scale (Juul‐Kristensen et al., 2017).

2.3.2. Measurements of signs of central sensitization

In this study central sensitization is defined as ‘an amplification of neural signalling within the central nervous system that elicits pain hypersensitivity’ (Woolf, 2011). This broader definition was chosen since it does not only consider central sensitization to be a spinal process but also involves more complex neuroplastic changes throughout the central nervous system (Woolf, 2011). This broader interpretation includes heightened sensitivity to various sensory stimuli, such as touch, light, and sound, as well as widespread pain beyond the primary injured area (Nijs et al., 2010).

Pressure hyperalgesia was assessed using PPTs measured on the dominant side at: (1) Trapezius muscle: sitting position, arms relaxed next to the body, midway between processus spinosus of C7 and the acromion; (2) Deltoid muscle: sitting position, arms relaxed next to the body, center of muscle in line of the axilla; (3) Tibialis anterior muscle: supine position, leg supported by towel/knee roll, midway between malleolus lateralis and fibula head, lateral to tibia; (4) Paraspinal muscles lower back: prone position, hands next to the body with palms up, 3 cm lateral to processus spinosus of L3; using a handheld digital pressure algometer (Wagner Instruments, FPX 25) (Duarte et al., 2000). Participants' PPTs were determined by gradually increasing the pressure provided by the algometer at a rate of 1 kg/s with a 1 cm2 rubber tip positioned at a 90degree angle relative to the body part being assessed, until the point when the sensation first became painful. The participants were instructed to say ‘stop’ at this point, and the pressure value was noted. This procedure was repeated three times at each site with a 30‐s interval between measurements (Duarte et al., 2000; Schubert‐Hjalmarsson et al., 2023). PPT was calculated as the mean of the last two values, a reliable approach in both children and adults (Duarte et al., 2000).

EIH was assessed by repeating PPT measures after participants performed an exercise test on a bicycle ergometer (Monark Ergomedic 828E). Participants cycled at a steady pace of 50 revolutions per minute, with initial resistance of 25 watts and resistance increasing by 25 watts every minute. Cycling stopped when they reached 75% of their expected maximum heart rate (i.e. 220 beats per minute minus their age in years) (Polar Heart rate sensor H10), fulfilling the full minute (Furzer et al., 2012). The protocol was adapted so that participants continued cycling until they reported a score of 15 on the Borg Rating of Perceived Exertion Scale (Borg RPE) 6–20, with 6 = ‘no exertion’ and 20 = ‘maximal exertion’ (Borg, 1982), to achieve a ‘strenuous’ level of exertion. Maximal exercise‐capacity values, including peak heart rate and self‐estimated exhaustion, were then recorded. The sequence of PPT measurement points before and after exercise was randomized, using www.jerrydallal.com to generate the randomization list for each participant in both groups.

EIH effect was calculated by subtracting the average PPT before exercise from the average PPT after exercise. A positive value indicates pain inhibition or normal EIH response, whereas a negative value indicates a reduction in pain threshold, demonstrating pain facilitation or impaired EIH response.

The Numerical Rating Scale (NRS) ranging from 0 to 10 (0 = ‘no pain,’ 10 = ‘worst possible pain’) was used to measure the average pain intensity following the cycling test (Dworkin et al., 2005; Miro et al., 2009).

2.4. Questionnaires

2.4.1. Socio‐demographic and background information

Socio‐demographic and relevant background data were collected using a self‐developed questionnaire, covering areas such as pain duration and frequency.

2.4.2. Pain localization

The pain drawing displayed full body images from front and back and was used to capture pain localization on the day of investigation, and any distribution of widespread pain. Participants marked areas of pain and indicated pain frequency as always, sometimes, or rarely. The body image was divided into quadrants: left and right side, upper and lower segments, and axial regions (cervical spine, chest, thoracic spine, lower back, stomach) (Butler et al., 2016; Wolfe et al., 2010). The presence of pain was assessed counting the number of pain locations, affected quadrants and axial regions. Pain occurrence was graded as follows: 0 = ‘no pain’, 1 = ‘localized pain in a few joints’, 2 = ‘increased pain in one to two quadrants and axial areas in at least 5 places’, and 3 = ‘widespread pain in three or more quadrants and axial regions’ (Butler et al., 2016). Only pain reported as ‘always’ or ‘sometimes’ was considered.

2.4.3. Fatigue

Fatigue was assessed using the Pediatric Quality of Life Multidimensional Fatigue Scale (PedsQL‐MFS) (Varni et al., 2002). The standard version with a one‐month recall period was used. In this study, the child's self‐report for ages 13–18 was used. PedsQL‐MFS comprises 18 questions divided into three subscales: general fatigue, sleep/rest fatigue, and cognitive fatigue, each with six questions. Responses range from 0 (never a problem) to 4 (almost always a problem), converted to a 0–100 scale. Higher scores indicate less fatigue. The scale demonstrates good reliability and validity in paediatric rheumatology (Varni et al., 2004).

2.4.4. Cognitive and emotional factors

The Pain Catastrophizing Scale for children (PCS‐C) assesses catastrophic thoughts in children and adolescents with pain (Crombez et al., 2003). It comprises 13 statements beginning with ‘When I have pain…’. The scale includes three subscales: rumination (4 statements), magnification (3 statements), and helplessness (6 statements). Responses range from 0 (not at all) to 4 (extremely), with scores ranging from 0 to 52. Higher scores indicate greater catastrophizing. The PCS‐C demonstrates good to excellent internal consistency and predictive as well as concurrent validity (Kemani et al., 2019; Kimura et al., 2014; Parkerson et al., 2013).

The Hospital Anxiety and Depression Scale (HADS) assesses anxiety and depression symptoms (Zigmond & Snaith, 1983). It comprises 14 statements with four response options, scored from 0 (lowest) to 3 (highest). Divided into anxiety and depression subscales, each subscale ranges from 0 to 21. HADS asks for cognitively related anxiety and depression symptoms with a 7‐day recall period. Higher scores indicate greater emotional involvement. The HADS has been adapted into multiple languages and used across various physical conditions, demonstrating adequate reliability and validity in paediatric patients (Saboonchi et al., 2013; Uljarević et al., 2018; Valero‐Moreno et al., 2019).

2.5. Statistical analysis

A priori power analysis was performed for sample size estimation with an alpha of 0.05 and strength 0.80. The analysis was based on data from a previous study regarding hyperalgesia in adolescents with HSD/hEDS at the same clinic, where PPTs from 10 patients with HSD/hEDS were compared with 9 healthy matched controls (Schubert‐Hjalmarsson et al., 2023). Power for the primary endpoint was calculated using the mean PPT value at the tibialis anterior muscle calculated using G*Power 3.1.9.2, with ‘family t‐tests’ − Means: Wilcoxon‐Mann–Whitney test (two groups), one tail, α = 0.05 and power 0.80, leading to an effect size of d = 0.58. The total sample size for comparisons between groups was calculated to be n = 40 participants per group and thus n = 80 in total, with an estimated dropout of 4 participants, the total sample size was set to n = 84.

Control for normal distribution was carried out for descriptive data and questionnaires with the Shapiro–Wilk test and PP‐plot. Interval data, quote data and ordinal data were reported as median, min‐max, and interquartile range (IQR). A general linear model was used to adjust the data for age, sex, Body Mass Index (BMI), and group affiliation to calculate between‐subjects effects for each variable as the dependent variable. To control for normal distribution the standardized residuals were presented in a PP‐Plot. To meet the skewed distribution of the data for PPTs, before and after exercise data were transformed to log data. The same general linear model was used for the calculation of the difference between groups for EIH. Wilcoxon Signed Rank Test was performed to analyse differences in PPTs before and after exercise within the same group. The between‐group analysis for ordinal data was performed with the Mann–Whitney‐Test (MWU). Estimate of effect size is provided in Cohen's d (d) and partial η 2 and R 2 for the general linear model. The Bonferroni test was used for correction of multiple testing for cognitive and emotional factors. Statistical analysis was carried out with IBM SPSS statistic 28 (Statistical Package for the Social Sciences) (IBM SPSS Data Collection).

3. RESULTS

3.1. Socio‐demographic and background information

A total of 176 adolescents with HED/hEDS and 111 healthy adolescents for the control group were invited to participate. Fifty‐nine adolescents with HED/hEDS and 56 adolescents in the control group accepted to participate. Twenty‐two participants in the HED/hEDS group were excluded, of which seven withdraw, three failed to attend, and 12 did not meet neither HSD, nor hEDS criteria according to the 2017 diagnostic criteria. Nine participants in the control group were excluded, of which three withdraw, two failed to attend, two met the diagnostic criteria for HSD, and two indicated pain on the day of examination with an NRS value >3 (Figure 1). This leads to a total of 37 participants in the HED/hEDS group and 47 participants in the control group. The characteristics of the groups are described in Table 1.

FIGURE 1.

FIGURE 1

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Flow diagram of participants.

TABLE 1.

Description of the study population.

HSD/hEDS group (n = 37) Median (IQR) Control group (n = 47) Median (IQR) Test statistics a p value a
Age (years) 16.4 (14.8–17.0) 15.3 (14.0–16.2) 615.5 0.022*
Beighton score, 0–9 6 (4–7) 2 (1–4) 314.0 < 0.001*
Beighton score, male 5 (2–6) n = 10 1 (0–3) n = 13 18.5 0.003*
Beighton score, female 6 (4–7) n = 27 2 (2–4) n = 34 164.5 < 0.001*
Length in metres 1.7 (1.6–1.7) 1.7 (1.6–1.8) 701.5 0.130
Weight, kg 58.5 (50.8–72.9) 59.0 (52.1–67.5) 854.0 0.889
BMI, kg/m2 21.2 (18.5–25.6) 20.0 (18.9–23.4) 732.5 0.217
Number (%) Number (%)
Sex Male 10 (27) 13 (28) 864.0 0.949
Female 27 (73) 34 (72)
Occasions of planned physical activity/week
0 10 (27.0) 12 (25.5)
1–2 18 (48.6) 12 (25.5)
≥3 9 (24.3) 23 (48.9)
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Abbreviations: BMI, body mass index, IQR, inter quartile range.

a

Mann Whitney U Test—group differences.

*

Statistically significant at α = 0.05.

There were no statistically significant differences between the groups in terms of sex distribution (p = 0.949) or BMI (p = 0.217). The adolescents with HSD/hEDS were older (p = 0.017) and had a higher Beighton score (p < 0.001) than the control group.

Pain intensity was significantly higher over the previous week (p < 0.001) and at the time of assessment (p < 0.001) in the HSD/hEDS group (Table 2). Characteristics of pain are presented in Table 2. When evaluating the pain drawing, the areas where participants indicated pain as ‘always’ or ‘sometimes’ were considered. Most adolescents in the control group had no pain (75%) or only local pain (25%), while most (82%) of adolescents with HSD/hEDS indicated pain, 22% in several body quadrants and 60% widespread pain (Table 2).

TABLE 2.

Pain characteristics of the study population.

HSD/hEDS group (n = 37) Control group (n = 47) Test statistics a Estimate of effect size b p value a
Pain intensity (NRS) Median (IQR) Median (IQR)
Over the past week 5 (3–6) 0 (0–2) 114.5 2.215 <0.001*
At the assessment 3 (2–5) 0 (0–0) 132.5 2.102 <0.001*
Pain Duration Number (%) Number (%)
No pain 0 33 (70)
Less than 3 months 0 3 (6)
3–6 months 1 (3) 3 (6)
More than 6 months 36 (97) 8 (17)
Pain Frequency Number (%) Number (%)
None 1 (3) 26 (55)
Some time each month 5 (14) 9 (19)
Several times each month 0 12 (26)
Several times each week 6 (16) 0
Several times each day‐ persistent 25 (68) 0
Pain Localization c Number (%) Number (%)
None 1 (3) 35 (75)
Local pain d 6 (16) 12 (25)
1–2 body quadrants e and axially f (at least 5 places) 8 (22) 0
Widespread pain = pain in 3 or more body quadrants (at least 5 places) and axially 22 (60) 0
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Abbreviation: IQR, inter quartile range; NRS, numerical rating scale.

a

Mann Whitney U Test– group differences.

b

Cohen‘s d.

c

Pain drawing, localization of pain in the past 3 months.

d

Local pain = pain in a maximum of 2 joint pairs or 1 joint pair and 1 place axially or maximum 3 axial places.

e

Body quadrants = upper–lower/left–right side of the body.

f

Axially = neck, back, chest, and abdomen.

*

Statistically significant at α = 0.05.

3.2. Measurements of signs of central sensitization

3.2.1. Generalized hyperalgesia

Adolescents with HSD/hEDS presented significantly lower PPTs in all examined muscle groups (Trapezius: p < 0.001; Deltoideus: p = 0.015: Tibialis anterior p = 0.045 and paraspinal muscles lower back: p = 0.021) compared to the healthy control group (Table 3).

TABLE 3.

Signs of generalized hyperalgesia and exercise induced hypoalgesia (EIH).

HSD/hEDS group (n = 37) Median (IQR) Control group (n = 47) Median (IQR) Partial η 2 R 2 p value a
Pressure pain threshold (kg/cm2)
Trapezius muscle 2.06 (1.57–3.07) 3.68 (2.33–4.54) 0.156 0.165 <0.001*
Tibialis anterior 3.82 (2.59–6.1) 5.31 (3.64–7.97) 0.050 0.058 0.045*
Deltoideus muscle 1.77 (1.07–2.52) 2.31 (1.42–3.91) 0.072 0.096 0.015*
Lower back, L3 2.66 (1.73–5.78) 4.27 (2.56–5.95) 0.065 0.078 0.021*
Pressure pain threshold (kg/cm2) after exercise
Trapezius muscle 2.26 (1.61–3.13) 3.73 (2.14–5.37) 0.154 0.164 <0.001*
Tibialis anterior 4.85 (3.26–7.60) 6.47 (4.70–9.65) 0.087 0.092 0.008*
Exercise‐induced hypoalgesia effect (kg/cm2) Test statistic b Estimate of effect size c p value b
Trapezius muscle 0.10 (−0.24–0.58) 0.25 (−0.12–0.57) 817 0.103 0.636
Tibialis anterior 0.33 (−0.31–1.22) 1.30 (0.08 2.38) 610 0.528 0.019*
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Abbreviation: IQR, inter quartile range; L3, lumbar vertebrae no. 3.

a

Based‐on log data, adjusted for age, sex, Body Mass Index and group affiliation.

b

Mann Whitney U Test– group differences.

c

Cohen's d.

*

Statistically significant at α = 0.05.

3.2.2. Exercise induced hypoalgesia

All participants completed the exercise protocol. The adolescents with HSD/hEDS cycled for a significantly shorter time (p = 0.005). There was no significant difference in the heart rate at the end of the exercise test (p = 0.093) nor on the Borg score (p = 0.477) (Table 4).

TABLE 4.

Results of the exercise protocol.

HSD/hEDS group (n = 37) median (IQR) Control group (n = 47) median (IQR) Test statistics a Estimate of effect size b p value a
Heart rate at end of the test, beats per minute 161.0 (156.5–171.5) 167.0 (162.0–171.0) 683 0.373 0.093
Borg RPE, 6–20 16.0 (15.0–17.5) 17.0 (15.0–17.0) 794 0.149 0.477
Cycling duration, minutes 4.52 (3.9–5.4) 5.40 (4.6–6.3) 556 0.648 0.005*
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Abbreviation: Borg RPE, Borg rating of perceived exertion scale; IQR, inter quartile range.

a

Mann–Whitney U Test– group differences.

b

Cohen's d.

*

Statistically significant at α = 0.05.

Data presented in this section show the median PPT values per muscle. Min‐max and quartiles for each muscle are shown in Table 3. In both groups, increased PPTs were found after exercise. In the HSD/hEDS group, there was no significant difference (p = 0.148) in PPT at the trapezius muscle between before (2.06 kg/cm2) and after (2.26 kg/cm2) the exercise. At the tibialis anterior muscle, the PPT significantly increased from 3.82 kg/cm2 to 4.85 kg/cm2 (p = 0.033). In the control group the PPT at the trapezius muscle changed from 3.68 to 3.73 kg/cm2 (p = 0.016) and in the tibialis anterior from 5.31 kg/cm2 to 6.47 kg/cm2 (p < 0.001), showing a significant increase at both sites (Table 5, Figure 2).

TABLE 5.

Pain Pressure Thresholds (PPT) before and after exercise—within group differences.

PPT before exercise median (IQR) PPT after exercise median (IQR) Z value a Estimate of effect size b p value a
Trapezius muscle
HSD/hEDS group (n = 37) 2.06 (1.57–3.07) 2.26 (1.61–3.13) −1.448 0.490 0.148
Control group (n = 47) 3.68 (2.33–4.54) 3.73 (2.14–5.37) −2.398 0.747 0.016*
Tibialis anterior muscle
HSD/hEDS group (n = 37) 3.82 (2.59–6.10) 4.85 (3.26–7.60) −2.127 0.746 0.033*
Control group (n = 47) 5.31 (3.64–7.97) 6.47 (4.70–9.65) −4.507 1.745 < 0.001*
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Abbreviation: IQR, inter quartile range.

a

Wilcoxon Signed Rank Test within group differences.

b

Cohen's d.

*

Statistically significant at α = 0.05.

FIGURE 2.

FIGURE 2

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Pain pressure thresholds (PPT) before and after exercise per muscle group and group affiliation.

There was a significant difference between groups for PPTs after exercise in the tibialis anterior muscle (p < 0.008), with those with HSD/hEDS having a median of 4.85 kg/cm2 compared to the control group 6.47 kg/cm2. The difference between the groups on the trapezius muscle was smaller but still statistically significant in adolescents with HSD/hEDS 2.26 kg/cm2 versus the control group 3.73 kg/cm2 (p = 0.001) (Table 3).

Looking at the difference between the before and after PPT measurements, namely EIH, there is a significant difference in the tibialis anterior muscle (p = 0.019) but not in the trapezius muscle (p = 0.636) between the groups (Table 3, Figure 3).

FIGURE 3.

FIGURE 3

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Effect of exercise induced hypoalgesia (EIH) – between group differences.

3.3. Cognitive and emotional factors

Adolescents with HSD/hEDS showed significantly lower scores in all areas regarding fatigue (PedsQL‐MFS—general fatigue: p < 0.001; PedsQL‐MFS—sleep/rest fatigue: p = 0.007; PedsQL‐MFS—cognitive fatigue: p < 0.001) and significantly higher scores regarding pain catastrophizing (PCS‐C: p < 0.001), as well as HADS depression scores (HADS: p < 0.010) and HADS anxiety scores (HADS p = 0.007) compared to the control group (Table 5).

4. DISCUSSION

The aim of this study was to investigate signs and impact of central sensitization in adolescents with HSD/hEDS, if identified. The study was able to demonstrate generalized hyperalgesia, which could indicate central sensitization. Further, significant differences between the HSD/hEDS group and the control group were shown in terms of fatigue, pain, and cognitive‐emotional factors (Table 6).

TABLE 6.

Results of cognitive and emotional factors by group.

HSD/hEDS group (n = 37) Median (IQR) Control group (n = 47) Median (IQR) Test statistic a Estimate of effect size b p value a
PedsQL MFS general fatigue, 0–100 33 (21–46) 75 (58–92) 141.5 2.05 <0.001*
PedsQL MFS sleep/rest fatigue, 0–100 46 (31–56) 63 (46–75) 475.0 0.84 0.007*
PedsQL MFS cognitive fatigue, 0–100 46 (33–58) 75 (58–88) 375.0 1.11 <0.001*
PCS‐C, 0–52 17 (12–29) 4 (1–10) 234.0 1.60 <0.001*
HADS depression, 0–21 11 (7.5–15) 6 (2–10) 392.0 1.06 <0.001*
HADS anxiety, 0–21 5 (4–9) 2 (1–5) 396.5 1.05 0.007*
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Abbreviations: HADS, Hospital anxiety and depression scalepeds; IQR, inter quartile range; QL‐MFS, pediatric quality of life multidimensional fatigue scale; PCS‐C, pain catastrophizing scale – Children's version.

a

Mann–Whitney U – group differences.

b

Cohen's d.

*

Bonferroni statistically significant at α = 0.008.

We found that adolescents with HDS/hEDS were more sensitive to pressure on all four measured muscle groups, indicating generalized pressure hyperalgesia, which could indicate central sensitization. These findings confirm the results from previously conducted studies that demonstrated generally reduced PPTs in both adults and children/adolescents with HSD/hEDS. (Rombaut et al., 2014; Scheper, Pacey, et al., 2017). Scheper, Pacey, et al. (2017) found that generalized hyperalgesia is a factor that may predict HSD/hEDS. It was interpreted that symptoms in individuals with HSD/hEDS are triggered by a combination of repeated musculoskeletal injuries and an upregulated central nervous system (Scheper, Pacey, et al., 2017). Our research validates this, thus offering another diagnostic approach in paediatric care that may facilitate early intervention through lifestyle modification.

4.1. Exercise induced hypoalgesia

The results of the study indicate that the exercise that participants undertook did not stimulate EIH in the HSD/hEDS group in the remote (i.e. nonexercising) muscle group. In general, the hypoalgesic response appears to be less pronounced in the remote body part, which has previously been shown in healthy adults (Gomolka et al., 2019; Vaegter et al., 2019). Following the exercise protocol used in this study, a positive effect of exercise in the form of increased PPT directly after the exercise could be mostly demonstrated locally.

Both the study by De Wandele et al. (2022) and the current study showed a lower pain‐inhibiting effect in the exercising limb in the HSD/hEDS group in comparison to a control group (De Wandele et al., 2022). However, in the HSD/hEDS group, no difference was found in the muscle that was not actively involved in the activity. This suggests that a generalized inhibitory effect after an acute interval of exercise was not achieved in the HSD/hEDS group.

The varied presentation of pain within the HSD/hEDS group, as presented by the pain drawing, could influence EIH. Therefore, conducting an analysis comparing individuals with HSD/hEDS and widespread pain to a control group in a future study could provide valuable insights. If EIH is affected, even in the active muscle group, it prompts the question as to whether widespread pain, rather than localized joint pain in HSD/hEDS per se, is the primary factor contributing to reduced EIH. This raises the need for further investigation to determine whether widespread pain becomes the predominant issue requiring attention, despite HSD/hEDS being the initial cause.

4.2. Fatigue

We found that the HSD/hEDS group reported a significantly greater experience of fatigue than the control group in all three domains examined: general fatigue, sleep/rest fatigue, and cognitive fatigue. These findings are confirmed by the results of two other studies. Sommer et al. (2023) showed that children and adolescents in general have a high prevalence of fatigue (>20%), but that the prevalence of fatigue in children and adolescents with chronic pain was significantly higher (>36%) (Sommer et al., 2023). A study in children with heritable connective tissue disorders, including HSD/hEDS, showed increased fatigue overall, and additionally the subgroup of children with HSD/hEDS, had a higher prevalence of fatigue compared to the other subgroups (Warnink‐Kavelaars et al., 2021). A question that could not be answered in our study is whether fatigue occurs independently of pain or in connection with pain in adolescents with HSD/hEDS.

4.3. Cognitive emotional sensitization

In this study, the HSD/hEDS group scored significantly higher in catastrophic thoughts about pain, anxiety, and depression compared to the control group. These results corroborate findings from prior research, highlighting an elevated presence of cognitive‐emotional factors among adolescents with HSD/hEDS. A previous cohort‐based study on adolescents has shown that generalized joint hypermobility present at age 14 was associated with an increased risk of developing depression at age 18, especially in males (Eccles et al., 2022). Moreover, the same study showed that HSD was associated with depressive disorders, anxiety disorders, and the level of anxiety in 18‐year‐olds (Eccles et al., 2022).

In a 15‐year follow‐up study of adolescents and young adults aged 16–20 at baseline, Bulbena et al. (2011) showed an increased risk of developing anxiety‐related conditions in individuals with HSD (Bulbena et al., 2011). Additionally, García Campayo et al. (2010) described an increased incidence of panic disorders in adults with HSD in their case–control study, (García Campayo et al., 2010). Collectively, these studies underscore a heightened vulnerability among adolescents with HSD/hEDS toward anxiety or depression‐related conditions.

Broader medical research has also elucidated the impact of cognitive‐emotional factors on pain sensitivity. For instance, Tesarz et al. (2015) showed that adult patients with previous psychological trauma had generally lower pain thresholds, indicating that emotional factors can impact pain sensitivity (Tesarz et al., 2015). A recent study involving 250 adolescents/young adults aged 8–23 with chronic pain revealed that widespread pain was associated with other pain‐related outcomes such as pain catastrophizing, fatigue, anxiety, and depression (Sommer et al., 2023). These findings suggest that emotional factors may contribute to pain sensitivity independently of joint hypermobility related conditions.

In our study, adolescents with HSD/hEDS presented higher scores on PCS‐C and HADS, suggesting potential cognitive and emotional sensitization. This phenomenon may underlie heightened pain sensitivity and reduced EIH. Aligning with prior research, our findings imply that cognitive‐emotional factors may influence pain sensitivity among adolescents with HSD/hEDS. More knowledge is needed to determine whether there would be a difference between individuals with HSD/hEDS who have cognitive‐emotional overlays and those who do not, in terms of the effect of physical activity.

Clinicians should be aware that the pain‐inhibiting effect of physical activity may be altered in individuals with hEDS, potentially leading to increased pain after exercise. Increased sensitivity to pressure should be considered during examinations and manual treatments. Both increased generalized pain sensitivity and a reduced inhibitory effect of exercise may indicate changes in central pain facilitation, which could indicate the presence of central sensitization. Clinicians should therefore consider the role of central pain mechanisms beyond the muscles and joints. This study also highlights future research questions that could enhance our understanding of the complex pain experience often described by adolescents with HSD/hEDS.

4.4. Strengths and limitations

The strength of our study is the relatively large study group, among only a few studies on adolescents with HSD/hEDS, and with a comparable size to other such studies with populations of 29–47 (Mu et al., 2019; Scheper, Pacey, et al., 2017; Warnink‐Kavelaars et al., 2021).

Since we did not achieve our estimated sample size, the results of this study should be interpreted with caution and generalization may not be appropriate. Larger studies need to be conducted to obtain generalizable results.

Some of the adolescents received a diagnosis of HSD or hEDS before 2017, which led to the exclusion of some participants if they no longer met the diagnostic criteria of neither HSD nor hEDS. With this, we increased the reliability of population diagnosis. Since the results are based on as homogeneous groups as possible, the likelihood that the results are more representative for the patient group increases.

Participants were asked to refrain from analgesics for at least 24 h before measurement. This may have led to selection bias by excluding patients with higher pain levels. Participants were asked to avoid COX inhibitors because these medications alter pain interpretation by blocking the enzyme cyclooxygenase, which could affect the results of the pain measurements. Additionally, participants in the HSD/hEDS group were significantly older than the control group. Recruiting was particularly challenging for older adolescents in the control group. A general linear model was used to adjust for age, gender, and BMI.

In this study, we used an aerobic cycling test to achieve submaximal exercise, assessed by the participant achieving submaximal heart rate or Borg RPE 15. It has been shown that intra‐subject reliability between sessions was only significant when using a lactate threshold protocol, which we did not use, as compared to a more subjective assessment such as the Borg RPE (Vaegter et al., 2019). Nevertheless, there is the possibility that participants with poor physical fitness could have reached their lactate threshold during the cycling test. If considering a lactate threshold protocol in a future study, the potential impact of a skin breeching procedure in a potentially sensitized population should be taken into account.

The ambition was to have a pain‐free control group, which turned out to be difficult. About 25% of the control group indicated some pain (limited or occasional local pain). In comparison approximal 80% of the HSD/hEDS group had frequent or continuous pain spread over the body. That said, this variation in pain appearance reflects clinical reality and indicates that adolescents with HSD/hEDS, even when compared to a control group with low pain, show significantly different outcomes.

5. CONCLUSION

In this study, adolescents with HSD/hEDS exhibited possible signs of central sensitization, as suggested by generalized hyperalgesia observed through PPTs at various body sites and potentially dysfunctional EIH in one of the two measured muscle groups. Although there was a significant difference in the effect of exercise between groups, both groups achieved a significantly higher PPT after exercise in the muscle involved in the activity. In the remote muscle, the control group had a low PPT after exercise while the HSD/hEDS group showed no differences. These results indicate, when creating a treatment plan for patients with HSD/hEDS, that pain should not be considered solely as caused by peripheral impulses, but rather as a phenomenon that is influenced by different biopsychosocial factors in which central mechanisms also need to be taken into consideration. The results should be interpreted with caution due to the study size. It will be of interest if future studies investigated whether EIH manifested differently in a select group of adolescents with HSD/hEDS with chronic widespread pain.

AUTHOR CONTRIBUTIONS

All authors made a significant contribution toward the design of the study. ESH, A‐CS performed the data collection. ESH performed data analysis and data interpretation, with the support of AF, KI, A‐CS and ML. ESH, KI, ML conceptualized the study. ESH and ML developed the manuscript with support of KI, AF and A‐CS. All authors provided final approval for the manuscript version to be published. ML supervised the overall study.

FUNDING INFORMATION

This study was funded by Region Västra Götaland's Health and Medical Care Executive Board.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ACKNOWLEDGEMENTS

We would like to thank all the adolescents and families who participated in this study.

Schubert‐Hjalmarsson, E. , Fasth, A. , Ickmans, K. , Söderpalm, A.‐C. , & Lundberg, M. (2025). Exploring signs of central sensitization in adolescents with hypermobility Spectrum disorder or hypermobile Ehlers‐Danlos syndrome. European Journal of Pain, 29, e4754. 10.1002/ejp.4754

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