Pain in Ehlers-Danlos syndromes: manifestations, therapeutic strategies and future perspectives (2016)

Marco Castori


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.


"Contemporary treatment of chronic-recurrent pain in EDS is based on five pillars, i.e. education, painkillers, physical therapy, psychotherapy, and monitoring and prevention of pain-modulating comorbidities (Figure 6)."

 Marco Castori (2016) Pain in Ehlers-Danlos syndromes: manifestations, therapeutic strategies and future perspectives, Expert Opinion on Orphan Drugs, 4:11, 1145-1158, DOI: 10.1080/21678707.2016.1238302

Research Review (2013)

Re-Writing the Natural History of Pain and Related Symptoms in the Joint Hypermobility Syndrome/ Ehlers–Danlos Syndrome, Hypermobility Type

Marco Castori, Silvia Morlino, Claudia Celletti, Giulia Ghibellini, Michela Bruschini, Paola Grammatico, Carlo Blundo, and Filippo Camerota

Abstract Joint hypermobility syndrome (JHS) and Ehlers–Danlos syn- drome, hypermobility type (EDS-HT) are two clinically over- lapping connective tissue disorders characterized by chronic/ recurrent pain, joint instability complications, and minor skin changes. Fatigue and headache are also common, although are not yet considered diagnostic criteria. JHS/EDS-HT is a unex- pectedly common condition that remains underdiagnosed by most clinicians and pain specialists. This results in interventions limited to symptomatic and non-satisfactory treatments, lacking reasonable pathophysiologic rationale. In this manuscript the fragmented knowledge on pain, fatigue, and headache in JHS/ EDS is presented with review of the available published infor- mation and a description of the clinical course by symptoms, on the basis of authors’ experience. Pathogenic mechanisms are suggested through comparisons with other functional somatic syndromes (e.g., chronic fatigue syndrome, fibromyalgia, and functional gastrointestinal disorders). The re-writing of the natural history of JHS/EDS-HT is aimed to raise awareness among clinical geneticists and specialists treating chronic pain conditions about pain and other complications of JHS/EDS-HT. Symptoms’ clustering by disease stage is proposed to investigate both the molecular causes and the symptoms management of JHS/EDS-HT in future studies. 

Castori M, Morlino S, Celletti C, Ghibellini G, Bruschini M, Grammatico P, Blundo C, Camerota F. 2013. Re-writing the natural history of pain and related symptoms in the joint hypermobility syndrome/Ehlers– Danlos syndrome, hypermobility type. Am J Med Genet Part A 161A:2989–3004. 


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