Pain in Ehlers-Danlos syndromes: manifestations, therapeutic strategies and future perspectives
Abstract
Introduction: Ehlers-Danlos syndrome (EDS) groups together an increasing number of hereditary soft connective tissue disorders. Among the most common variants, the hypermobility type emerges as the most problematic, due to clinical similarities with the joint hypermobility syndrome, strong association with pain and lack of molecular confirmatory tests. To date, chronic pain and the related physical disability are the most relevant clinical issues in the long-term management of EDS.Areas covered: A literature review was carried out covering all known pain manifestations, i.e. musculoskeletal pain, neuropathic pain, central sensitization, headache and visceral pain, in EDS. The natural history of pain, as well as other critical issues, i.e. heterogeneity, clinical approach and evolving phenotype, of EDS are also addressed. All available data on therapeutic strategies for pain in EDS are extensively reported.Expert opinion: Multidisciplinarity emerges as an undeniable prerequisite for the management of the complex EDS patient reporting pain. All available therapeutic resources, comprising painkillers, physical and psychological therapies, and surgery, show a low evidence of efficacy in the long-term treatment of pain. Education and early diagnosis are primary resources for secondary and tertiary prevention. Novel drug therapies could be developed considering the potential role of a dysfunctional extracellular matrix on pain modulation in EDS.
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Orthopedic procedures are indicated for pain relief in only selected patients with EDS.
“orthopedic procedures are indicated for pain relief in only selected patients [29].”
From Psychological interventions for individuals with Ehlers-Danlos syndrome and hypermobility spectrum disorder: a scoping review (2023) · cites this paper as [29]
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Thumb Carpometacarpal Joint Stabilization in Ehlers-Danlos Syndrome - Case Report
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A framework for the classification of joint hypermobility and related conditions
Castori, M., Tinkle, B., Levy, H., Grahame, R., Malfait, F., & Hakim, A. (2017) · American Journal of Medical Genetics Part C: Seminars in Medical Genetics · doi:10.1002/ajmg.c.31539 · Cited by 602 · see citing works
“The development of chronic pain is sometimes a long-term complication of JH [Castori, 2016].”
BackgroundSelf-citationContemporary approach to joint hypermobility and related disorders
Castori, M., & Hakim, A. (2017) · Current Opinion in Pediatrics · doi:10.1097/mop.0000000000000541 · Cited by 105 · see citing works
Self-citationBaeza-Velasco, C., Bulbena, A., Polanco-Carrasco, R., & Jaussaud, R. (2019) · Disability and Rehabilitation · doi:10.1080/09638288.2017.1419294 · Cited by 51 · see citing works
“More research is needed to identify an optimal non-pharmacological approach to pain management in EDS-H [14].”
BackgroundInfluentialSchubart, J. R., Schaefer, É., Janicki, P., Adhikary, S. D., Schilling, A. L., Hakim, A. J., Bascom, R., Francomano, C. A., & Raj, S. R. (2019) · Journal of Dental Anesthesia and Pain Medicine · doi:10.17245/jdapm.2019.19.5.261 · Cited by 46 · see citing works
“Many people with EDS live with chronic pain and high anxiety [33] and often experience a phenomenon known as “wind-up pain”, with prolonged, persistent release of neurotransmitters involved in pain pathways.”
BackgroundManagement of chronic pain in Ehlers–Danlos syndrome: Two case reports and a review of literature
Zhou, Z., Rewari, A., & Shanthanna, H. (2018) · Medicine · doi:10.1097/md.0000000000013115 · Cited by 46 · see citing works
“The recurrent dislocations due to joint laxity and associated trauma are further amplified by poor proprioception.([1,2,5]) The fear of falling and kinesiophobia are common complaints.”
BackgroundInfluentialRecognizing and Effectively Managing Hypermobility-Related Conditions
Russek, L. N., Stott, P., & Simmonds, J. V. (2019) · Physical Therapy · doi:10.1093/ptj/pzz078 · Cited by 40 · see citing works
A review of Ehlers-Danlos syndrome
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Glayzer, J. E., McFarlin, B. L., Castori, M., Suarez, M. L., Meinel, M., Kobak, W. H., Steffen, A. D., & Schlaeger, J. M. (2021) · American Journal of Medical Genetics Part C Seminars in Medical Genetics · doi:10.1002/ajmg.c.31939 · Cited by 31 · see citing works
“, 2010) report difficulties performing activities of daily living (Castori, 2016).”
BackgroundInfluentialSelf-citationExercise and Rehabilitation in People With Ehlers-Danlos Syndrome: A Systematic Review
Buryk-Iggers, S., Mittal, N., Mina, D. S., Adams, S. C., Englesakis, M. F., Rachinsky, M., Lopez-Hernandez, L., Hussey, L., McGillis, L., McLean, L., et al. (2022) · Archives of Rehabilitation Research and Clinical Translation · doi:10.1016/j.arrct.2022.100189 · Cited by 30 · see citing works
Maya, T. R., Fettig, V. M., Mehta, L., Gelb, B. D., & Kontorovich, A. (2021) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.62446 · Cited by 26 · see citing works
Schubart, J. R., Schilling, A., Schaefer, E., Bascom, R., & Francomano, C. (2019) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.61031 · Cited by 26 · see citing works
“Fatigue, depression, and anxiety have been linked with one another in EDS (Voermans & Knoop, 2011), and may also play a role in intensifying pain in EDS (Castori, 2016; Syx et al., 2017; Voermans & Knoop, 2011).”
BackgroundInfluentialSchubart, J. R., Schaefer, É., Hakim, A. J., Francomano, C. A., & Bascom, R. (2019) · Journal of Pain and Symptom Management · doi:10.1016/j.jpainsymman.2019.05.013 · Cited by 24 · see citing works
Syx, D., Miller, R. E., Obeidat, A. M., Tran, P. B., Vroman, R., Malfait, Z., Miller, R. J., Malfait, F., & Malfait, A.-M. (2020) · Pain · doi:10.1097/j.pain.0000000000001935 · Cited by 19 · see citing works
“antidepressants, antiseizure medication, and muscle relaxants, or a combination thereof.(6,34,37,40,51) Yet, pain is largely refractory”
BackgroundNutritional Implications of Patients with Dysautonomia and Hypermobility Syndromes
Do, T., Diamond, S. J., Green, C., & Warren, M. M. (2021) · Current Nutrition Reports · doi:10.1007/s13668-021-00373-1 · Cited by 19 · see citing works
Albertz, M. L., Whitlock, P. W., Yang, F., Ding, L., Uchtman, M., Mecoli, M. D., Olbrecht, V. A., Moore, D. L., McCarthy, J. J., & Chidambaran, V. (2020) · Journal of Hip Preservation Surgery · doi:10.1093/jhps/hnab010 · Cited by 16 · see citing works
Ehlers-Danlos Syndromes, Joint Hypermobility and Hypermobility Spectrum Disorders
Micale, L., Fusco, C., & Castori, M. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-80614-9_9 · Cited by 16 · see citing works
Self-citationJoint hypermobility in children: a neglected sign needing more attention
Castori, M. (2020) · Minerva Pediatrics · doi:10.23736/s0026-4946.20.05766-7 · Cited by 10 · see citing works
Self-citationEseonu, K., Payne, K., Ward, S. P., Fakouri, B., & Panchmatia, J. R. (2021) · The International Journal of Spine Surgery · doi:10.14444/8067 · Cited by 9 · see citing works
“Recommendations based on the efficacy of pain medications for use in the treatment of hypermobility are limited by lack of evidence.(32) An international consortium has published recent literature on commonly used medication strategies.”
BackgroundSong, J. Z., Luong, D., Feldman, E. C. H., Tran, S., Perrier, L., Eubanks, K., Bayley, M., Kastner, M., Slepian, M., & Munce, S. E. P. (2023) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-023-02799-y · Cited by 9 · see citing works
“In addition, individuals with EDS experience increased side effects of pain medications [28]; orthopedic procedures are indicated for pain relief in only selected patients [29].”
BackgroundA qualitative study of pain and related symptoms experienced by people with Ehlers-Danlos syndromes
Schubart, J. R., Mills, S. E., Francomano, C. A., & Stuckey, H. L. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2023.1291189 · Cited by 8 · see citing works
Robbins, K. (2022) · Nursing for Women s Health · doi:10.1016/j.nwh.2022.03.005 · Cited by 6 · see citing works
Ehlers-Danlos Syndrome: It’s Not Your Normal Hoofbeats
Hein, L. C., DeGregory, C., & Umari, F. (2019) · The Journal for Nurse Practitioners · doi:10.1016/j.nurpra.2019.01.006 · Cited by 6 · see citing works
Neurobiological and neuropsychological disturbance in EDS
Westerman, M., Kafkas, A., Parry‐Jones, A., Strong, S., Retzler, C., & Hallam, G. (2025) · Frontiers in Neurology · doi:10.3389/fneur.2025.1648702 · Cited by 5 · see citing works
Lattimore, P. J., & Harrison, F. (2022) · Disability and Rehabilitation · doi:10.1080/09638288.2022.2140843 · Cited by 5 · see citing works
Molander, P., Novo, M., Ringqvist, Å., Hållstam, A., Hesser, H., Löfgren, M., Stålnacke, B., & Gerdle, B. U. C. (2024) · Journal of Rehabilitation Medicine · doi:10.2340/jrm.v56.12431 · Cited by 8 · see citing works
“Chronic pain in EDS and HSD includes different components of nociceptive, neuropathic and nociplastic mechanisms (6), and thus the pain is generally complex and often generalized.”
Chuchin, J., & Ornstein, T. J. (2023) · Disability and Rehabilitation · doi:10.1080/09638288.2023.2268520 · Cited by 4 · see citing works
“Pain catastrophizing and fear-avoidance beliefs have been reported in individuals with hallmark hypermobility and pain [20].”
Halverson, C. M. E., & Doyle, T. A. (2023) · Disability and Rehabilitation · doi:10.1080/09638288.2023.2200039 · Cited by 3 · see citing works
“While several previous studies have examined this topic from the perspectives of clinicians [28,29], our data provide distinctive insight by examining it from the perspective of the patients themselves.”
ResultMałecki, K., Fabiś-Strobin, A., Sałacińska, K., Kwas, K., Stelmach, W., Beczkowski, J., Niedzielski, K. R., & Gach, A. (2023) · Scientific Reports · doi:10.1038/s41598-023-49378-6 · Cited by 3 · see citing works
“From a clinical perspective, this is of interest to mainly orthopaedic and trauma surgeons, physiotherapists and geneticists 1,3–5 .”
BackgroundВикторовна, С. С., Svistushkin, V. M., Avetisyan, E. Y., Shadyev, T. H., & Александрович, К. П. (2023) · Meditsinskiy sovet = Medical Council · doi:10.21518/ms2023-378 · Cited by 1 · see citing works
Creatine Monohydrate as an Effective Supplement for Muscular Fatigue in an Ehlers-Danlos Patient
Behringer, C. R., & Afrin, S. (2024) · Cureus · doi:10.7759/cureus.61721 · Cited by 1 · see citing works
“The syndrome primarily affects the joints and skin [2] and results in osteoarticular pain [3].”
BackgroundComorbid Conditions of Ehlers–Danlos Syndromes and Vulvodynia: A Latent Class Analysis
Glayzer, J. E., Bray, B. C., Kobak, W. H., Trujillo, C., Patil, C. L., Li, H., Francomano, C. A., & Schlaeger, J. M. (2026) · Pain Management Nursing · doi:10.1016/j.pmn.2026.03.005 · Cited by 1 · see citing works
“…et al., 2017) resulting in joint hypermobility; skin fragility; defective scarring; vascular and internal organ fragility prone to ruptures, gastroparesis, dysautonomia, and prolapse (Castori, 2016; Castori et al., 2015; Malfait et al., 2017; B. Tinkle et al., 2017; B.T. Tinkle & Levy, 2019).”
Emerging Clinical Concepts in Pain Management of Ehlers-Danlos Syndrome
Banerjee, R. C., Ramsey, M. E., Buras, B. E., Potharaju, P., Shekoohi, S., Abd-Elsayed, A. A., & Kaye, A. D. (2026) · Current Pain and Headache Reports · doi:10.1007/s11916-026-01532-1 · Cited by 1 · see citing works
“The genetic cause of hEDS has not yet been clearly identified, unlike other EDS subtypes that [13, 20, 22, 23].”
InfluentialGenetics and Periodontal Disease: An Explicit Insight
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Introduction: An overview of the Ehlers-Danlos syndromes and hypermobility spectrum disorders
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Parasympathetic and Sympathetic Nervous System Dysfunction and Monitoring
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“In GJH, generalized connective-tissue laxity permits joint motion beyond normal limits and may contribute to recurrent instability and chronic, widespread musculo-skeletal pain [5–7].”
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Headache in patients with joint hypermobility
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“5,11 When symptomatic JH does not meet criteria for a de fi ned hereditary connective tissue disorder, the term Hypermobility Spectrum Disorders (HSD) is applied (Table 1).”
- Authors
- Castori, M.
- Affiliations
- Azienda Ospedaliera San Camillo-Forlanini (IT)
- Corresponding author
- Castori, Marco
- ORCID
- Castori, Marco
- Venue
- Expert Opinion on Orphan Drugs
- Publisher
- Informa UK Limited
- Published
- 2016-09-27
- Volume
- 4
- Issue
- 11
- Pages
- 1145-1158
- ISSN
- 2167-8707 (ISSN-L)
- OpenAlex
- W2521486061
- Cited by
- 46
- References
- 130
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 7 · 2023: 7 · 2022: 3 · 2021: 6 · 2020: 4 · 2019: 6 · 2018: 2 · 2017: 3
- FWCI
- 2.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Expert Opinion on Orphan Drugs (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Health Sciences › Medicine › Pharmacology › Musculoskeletal pain and rehabilitation
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Keywords
- Ehlers-Danlos syndrome, chronic pain, hypermobility type, joint hypermobility syndrome, musculoskeletal pain, neuropathic pain, central sensitization, headache, visceral pain, pain management, multidisciplinary care, pain modulation, early diagnosis, secondary and tertiary prevention
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