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Because experimental pain testing in hEDS is scarce, the underlying mechanisms are still poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>The present study assesses endogenous pain facilitation and pain inhibition in hEDS, using a protocol for temporal summation of pain (TSP), conditioned pain modulation (CPM) and exercise\u2010induced hypoalgesia (EIH).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Twenty women with hEDS and 20 age\u2010matched healthy controls participated. After evaluating thermal and mechanical pain thresholds (PPT), TSP was assessed using 10 repetitive painful pressure stimuli. CPM was provoked using pressure as the test stimulus and hand immersion in hot water (46\u00b0) as the conditioning stimulus. EIH was assessed after a submaximal cycling protocol.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The hEDS group demonstrated reduced PPTs and showed significantly more TSP after repeated painful stimuli than the control group. In comparison to the healthy control group, the hEDS group demonstrated significantly less EIH at the quadriceps test location. At the trapezius, EIH did not significantly differ between groups. No significant differences were found between the hEDS group and control group in the CPM response.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The results demonstrate increased TSP in hEDS, suggesting increased central pain facilitation. EIH should be studied more extensively but may be disturbed when evaluated in the muscles that are activated during exercise. The CPM results are inconclusive and require more research.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Studies regarding the mechanisms that underlie pain in hEDS are scarce, although it is the most prevalent and disabling symptom in this patient population. This study demonstrates increased temporal summation in hEDS and suggests that exercise\u2010induced hypoalgesia may be reduced. Because exercise is a cornerstone in the multidisciplinary treatment of heritable connective tissue disorders, gaining knowledge in this field is important. Pressure stimuli were used to facilitate the international usability of the protocols, allowing for future data acquisition in large cohorts.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ejp.1956","type":"journal-article","created":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T14:55:52Z","timestamp":1650466552000},"page":"1355-1367","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Exploring pain mechanisms in hypermobile <scp>Ehlers\u2010Danlos<\/scp> syndrome: A case\u2013control study"],"prefix":"10.1002","volume":"26","author":[{"given":"Inge","family":"De Wandele","sequence":"first","affiliation":[{"name":"Center for Medical Genetics Ghent University and Ghent University Hospital  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlies","family":"Colman","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Ghent University and Ghent University Hospital  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