Neuropathic Pain Is a Common Feature in Ehlers-Danlos Syndrome

Abstract

Ehlers-Danlos syndrome (EDS) is a clinically variable and genetically heterogeneous group of heritable connective tissue disorders, mainly characterized by joint hypermobility, skin hyperextensibility, and vascular and internal organ fragility.1Callewaert B. Malfait F. Loeys B. De Paepe A. Ehlers-Danlos syndromes and Marfan syndrome.Best Pract Res Clin Rheumatol. 2008; 22: 165-189Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar Chronic pain is an extremely variable but highly frequent finding in EDS.2Castori M. Camerota F. Celletti C. et al.Natural history and manifestations of the hypermobility type Ehlers-Danlos syndrome: a pilot study on 21 patients.Am J Med Genet A. 2010; 152A: 556-564Crossref PubMed Scopus (138) Google Scholar, 3Grahame R. Joint hypermobility syndrome pain.Curr Pain Headache Rep. 2009; 13: 427-433Crossref PubMed Scopus (65) Google Scholar, 4Sacheti A. Szemere J. Bernstein B. et al.Chronic pain is a manifestation of the Ehlers-Danlos syndrome.J Pain Symptom Manage. 1997; 14: 88-93Abstract Full Text PDF PubMed Scopus (126) Google Scholar, 5Voermans N.C. Knoop H. Bleijenberg G. van Engelen B.G. Pain in Ehlers-Danlos syndrome is common, severe, and associated with functional impairment.J Pain Symptom Manage. 2010; 40: 370-378Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar Additional features, such as kinesiophobia, fatigue, anxiety, and depression, are equally common and, very probably, represent late consequences of an irreversible chronic pain syndrome, which, in turn, causes severe and progressive deterioration of physical activity and quality of life.6Lumley M.A. Jordan M. Rubenstein R. Tsipouras P. Evans M.I. Psychosocial functioning in the Ehlers-Danlos syndrome.Am J Med Genet. 1994; 53: 149-152Crossref PubMed Scopus (77) Google Scholar, 7Voermans N.C. Knoop H. van de Kamp N. et al.Fatigue is a frequent and clinically relevant problem in Ehlers-Danlos syndrome.Semin Arthritis Rheum. 2010; 40: 267-274Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 8Castori M. Camerota F. Celletti C. Grammatico P. Padua L. Quality of life in the classic and hypermobility types of Ehlers-Danlos syndrome.Ann Neurol. 2010; 67: 145-146Crossref PubMed Scopus (29) Google Scholar, 9Gurley-Green S. Living with the hypermobility syndrome.Rheumatology. 2001; 40: 487-489Crossref PubMed Scopus (33) Google Scholar Little is known about the origin and features of chronic pain in EDS. Pain is usually described as nociceptive (caused by ongoing stimulation of nociceptors) or neuropathic (caused by a primary lesion or dysfunction in the nervous system).10Merskey H. Bogduk N. Classification of chronic pain: Descriptions of chronic pain syndromes and definitions of pain terms. IASP press, Seattle, WA1994Google Scholar Nociceptive and neuropathic pains may respond variably to different types of drugs: the first to nonsteroidal anti-inflammatory drugs and similar medications and the second to antidepressants, antiepileptics, and opioids. To tailor the therapy, discrimination between nociceptive and neuropathic pain is needed. For this reason, in the routine practice of our multidisciplinary outpatient clinic dedicated to joint hypermobility, EDS patients are given specific pain tools to assess severity and discriminate the origin of pain to provide the most appropriate therapy. We enrolled 44 patients with the hypermobility and classic forms of EDS. Joint hypermobility was assessed using the Beighton score.11Beighton P. Solomon L. Soskolne C.L. Articular mobility in an African population.Ann Rheum Dis. 1973; 32: 413-418Crossref PubMed Scopus (1183) Google Scholar Diagnosis of the classic and hypermobility types of EDS was established according to the Villefranche and Brighton criteria.12Beighton P. De Paepe A. Steinmann B. Tsipouras P. Wenstrup R.J. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK).Am J Med Genet. 1998; 77: 31-37Crossref PubMed Scopus (1366) Google Scholar, 13Grahame R. Bird H.A. Child A. The revised (Brighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome (BJHS).J Rheumatol. 2000; 27: 1777-1779PubMed Google Scholar To assess occurrence, severity, and origin of pain, we administered a set of validated questionnaires: Numeric Rating Scale (NRS), the ID Pain™, and the Italian version of the Neuropathic Pain Symptom Inventory (NPSI).14Deschamps M. Band P.R. Coldman A.J. Assessment of adult cancer pain: shortcomings of current methods.Pain. 1988; 32: 133-139Abstract Full Text PDF PubMed Scopus (78) Google Scholar, 15Portenoy R. Development and testing of a neuropathic pain screening questionnaire: ID pain.Curr Med Res Opin. 2006; 22: 1555-1565Crossref PubMed Scopus (216) Google Scholar, 16Bouhassira D. Attal N. Fermanian J. et al.Development and validation of the neuropathic pain symptom inventory.Pain. 2004; 108: 248-257Abstract Full Text Full Text PDF PubMed Scopus (874) Google Scholar, 17Padua L. Briani C. Jann S. et al.Validation of the Italian version of the Neuropathic Pain Symptom Inventory in peripheral nervous system diseases.Neurol Sci. 2009; 30: 99-106Crossref PubMed Scopus (50) Google Scholar NRS is a numeric scale used to measure every kind of pain; ID Pain is a self-administered questionnaire to discriminate neuropathic from nociceptive pain, with a score (range from 1 to 5) that gives an incremental probability of suffering from neuropathic pain; NPSI is a self-administered questionnaire consisting of 10 descriptors that allows the clinician to discriminate and quantify dimensions of neuropathic pain. NPSI identifies five different subscores of pain: burning spontaneous, pressing spontaneous, paroxysmal, evoked, and paresthesia/dysesthesia. All questionnaires were scored as recommended by the developers.14Deschamps M. Band P.R. Coldman A.J. Assessment of adult cancer pain: shortcomings of current methods.Pain. 1988; 32: 133-139Abstract Full Text PDF PubMed Scopus (78) Google Scholar, 15Portenoy R. Development and testing of a neuropathic pain screening questionnaire: ID pain.Curr Med Res Opin. 2006; 22: 1555-1565Crossref PubMed Scopus (216) Google Scholar, 16Bouhassira D. Attal N. Fermanian J. et al.Development and validation of the neuropathic pain symptom inventory.Pain. 2004; 108: 248-257Abstract Full Text Full Text PDF PubMed Scopus (874) Google Scholar, 17Padua L. Briani C. Jann S. et al.Validation of the Italian version of the Neuropathic Pain Symptom Inventory in peripheral nervous system diseases.Neurol Sci. 2009; 30: 99-106Crossref PubMed Scopus (50) Google Scholar To evaluate differences in pain between the classic and hypermobility EDS groups, we used the nonparametric Mann-Whitney U test (Statistica®; StatSoft, Tulsa, OK). A P-value <0.05 was considered significant. Among the 44 selected subjects, 29 had the hypermobility type and 15 the classic type of EDS (Table 1). Assessment of pain in the whole sample and in the hypermobility and classic forms is reported in Table 1. Eighty-nine percent of patients complained of at least moderate pain (≥3 of 10 on NRS). According to the ID Pain, 68% of patients suffered from at least “probable” neuropathic pain (“probably” 32% and “likely” 36%). Duration of pain was greater than one year in all patients. Comparison of severity, origin, and symptoms between the hypermobility and classic forms did not show significant differences (Table 1).Table 1NRS, ID Pain™, and NPSI Values in the Whole Sample and in the Two Examined Types of Ehlers-Danlos SyndromeFeatureWhole SampleEDS Hypermobility TypeaDifferences between the classic and hypermobility types are all not significant.EDS Classic TypeaDifferences between the classic and hypermobility types are all not significant.Age (mean±SD)38.6±15.539.17±17.1537.53±12.15Males/females12/324/258/7NRS6.2±2.66.7±2.25.2±3ID pain2.22±1.652.34±1.712.06±1.7NPSI burning (superficial)3.0±3.313.34±3.302.33±3.30NPSI pressing (deep)3.49±2.823.96±2.582.56±3.09NPSI paroxysmal pain3.31±3.183.62±3.322.7±2.88NPSI evoked pain3.84±3.214.08±3.073.37±3.50NPSI paresthesia/dysesthesia3.84±3.104.0±2.923.53±3.49NPSI total17.48±12.7919.01±11.8514.51±14.38NPSI-FW1.73±1.331.81±1.261.56±1.48NPSI-FW=NPSI frequency weighted score; NS=not significant.a Differences between the classic and hypermobility types are all not significant. Open table in a new tab NPSI-FW=NPSI frequency weighted score; NS=not significant. To our knowledge, this is the first study that attempted to assess the type of pain in EDS. A major limitation of this work is the relatively small sample size. However, we decided to obtain data only from patients directly evaluated. This strategy was chosen essentially because, for such an elusive diagnosis as classic and hypermobility EDS, we believe that obtaining data from patients enrolled by telephone call or mail may represent a major bias. In addition, considering an overall prevalence of the disorder of one in 5000, our results are representative for a population of 220,000 individuals and, therefore, can be considered quite significant. Our preliminary findings are apparently in contrast with common sense, that is, in EDS, pain is directly linked to primary joint damage and, consequently, is mainly nociceptive in origin.18Grahame R. Heritable disorders of connective tissue.Best Pract Res Clin Rheumatol. 2000; 14: 345-361Abstract Full Text PDF PubMed Scopus (68) Google Scholar In fact, our results suggest that pain is frequently neuropathic. This implies that the pathophysiology of pain in EDS may be more complex than expected, and that musculoskeletal involvement cannot explain the entire spectrum of pain. Accordingly, it is likely that pain symptoms in EDS are the result of different pain-triggering mechanisms. The absence of significant differences between the classic and hypermobility types of EDS suggests that the two forms should equally be considered for a high risk of pain, and that they very probably share the same pathophysiology related to pain. Further studies in larger patient samples comparing patient-oriented pain assessments with neurophysiological studies are needed to clarify the many aspects of this disabling symptom. These investigations may be mainly focused on gender influences on pain, identification of specific cause(s) of neuropathic pain, and response to therapies. In the future, this kind of information may improve quality of life for EDS patients through a more tailored pain therapy.