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15 Articles in Volume 21, Issue #4
Advanced Practice Matters: Needs Assessment in Pain Management Training
Analgesics of the Future: Novel Capsaicin Formulation CNTX-4975
Ask the PharmD: How to Improve Medication Adherence in Chronic Pain Management
Behavioral Medicine: Applying Mindfulness-Based Stress Reduction for Comorbid Pain and PTSD
Case Report: Multimodal Management of Osteoarthritis
Commentary: The PCP's Role in Preventing Chronic Back Pain
Guest Editorial: Structural Racism in Pain Practice and How to Combat the “Hidden Curriculum”
Hypermobile Ehlers-Danlos Syndrome: An Update on Therapeutic Approaches for Pain Management
Male Clinicians as Allies in Women’s Leadership: What Your Female Peers Want You to Know
Meet the Women Changing Pain Medicine
Perspective: It’s Time to Advocate for Early Interventional Pain Management
Research Insights: Is Spinal Fusion Surgery Being Overused in Back Pain Care?
Tips from the Field: Treating Pain in an Under-Resourced State
Utilizing Music Therapy to Manage Chronic Pain
Woman to Woman: Leaders Share Advice for the Next Generation of Pain Medicine Clinicians

Hypermobile Ehlers-Danlos Syndrome: An Update on Therapeutic Approaches for Pain Management

Current evidence and clinical thinking on the benefits of physical activity and medication to manage chronic pain and daily function in patients with hEDS.

Ehlers-Danlos Syndrome (EDS) consists of a spectrum of distinct disorders primarily driven by genetic and molecular defects that has been increasingly investigated over the past decade. The subtypes of disorders that fall within EDS have been reclassified several times. Most recently, in 2017 a revised EDS classification system was developed by the International EDS Consortium recognizing 13 different subtypes of the disease.1

Importantly, each subtype shares many clinical features and underlying mechanisms. In addition, there can be commonalities between EDS subtypes and other connective tissue disorders. As a result, making a diagnosis and treating EDS can be clinically challenging.

This review distinguishes the most common subtype of EDS – hypermobile EDS (hEDS) – by etiology, diagnosis, and treatment.

Similar to other subtypes of EDS, hypermobile Ehlers Danlos Syndrome is known to be a heritable connective tissue disorder that has several clinical manifestations related to chronic pain. (Image: iStock)

Hypermobile Ehlers-Danlos Syndrome (hEDS): Pathology and Diagnosis

Similar to other subtypes of EDS, hEDS is known to be a heritable connective tissue disorder that has several clinical manifestations related to chronic pain.1,2 Although the exact prevalence of hEDS is largely unknown, it has been estimated that hEDS represents about 80% to 90% of all EDS subtypes, and collectively, all types of EDS have been reported as a minimum prevalence of 1 in 5,000.2,3

This specific EDS subtype is known to be inherited as autosomal dominant, however, unlike other types of EDS, there have not been any identified single genetic etiologies responsible for hEDS.2 Instead small evidence exists for the potential of several possible genetic factors including haploinsufficiency of tenascin X (an extracellular matrix protein that can potentially affect connective tissue),4,5 variations of collagen type III,6 and variations of the LZTS1 gene.7

The Three Phases of hEDS: Hypermobillity, Pain, Stiffness

The clinical features and symptomology of hEDS can consist of relatively general symptoms that seem to overlap with other connective tissue disorders and can evolve overtime. Specifically, a three-phase prototypical disease course has been described:

  1. hypermobility
  2. pain
  3. stiffness

However, not all patients experience all three phases and the rate of transition between phases can vary.2

The hypermobility phase is thought to affect primarily early life, clinically appearing with contortion-like ability, propensity for sprains, growing pains associated with fine motor repetitive tasks, fatigability, and even delay in gross and fine motor skills.2

The pain phase, which appears to be the most prevalent aspect of hEDS, occurs throughout the second to fourth decades of life and can be characterized by progressive and generalized chronic pain, usually manifesting as musculoskeletal and neuropathic in nature, however, it can specifically present as headaches, joint pain, and/or pelvic pain in women.2,8 There is some evidence to suggest development of hyperalgesia, which can further complicate symptoms and its management, as this can allow for central sensitization processes to occur.8-10 The pain phase can further be confounded by symptoms such as chronic fatigue, gastrointestinal issues, orthostatic intolerance, and pelvic dysfunction.2

Finally, the stiffness phase is notable for a chronic reduction of joint mobility, often allowing for significant reduction in physical activity and functionality, reduction in muscle mass, enhanced generalized weakness, defective proprioception, and arthritis.2 Although this phase typically presents later in life, as with all phases of hEDS, stiffness can certainly symptomize throughout all any age of life.2

Differentiating Overlapping Symptoms

Due to the range in symptoms found in hEDS, and the fact that many symptoms overlap with other pain disorders (including fibromyalgia, mixed connective tissue disorder, etc), diagnosing hEDS can be difficult and remains purely clinical. According to the most recent international classification, several criteria must be met to appropriately diagnose a patient with hEDS.1

Making an Official hEDS Diagnosis

Table I provides this criteria, which are especially important considering there has not been reliable or appreciable genetic etiology that can provide absolute confirmation.1




As detailed, patients must:

  • exhibit symptoms of generalized joint hypermobility (GJH; Criterion 1)
  • exhibit systemic manifestations of a more generalized connective tissue disorder or have a positive family history or exhibit musculoskeletal complications (all Criterion 2)
  • and be evaluated to exclude other EDS or connective tissue disorder diagnoses (Criterion 3).1

Although the exact mechanisms of underlying pain in hEDS are not well understood, they likely involve similar mechanisms to other forms of EDS. Pain management is approached similarly to that of other chronic pain disorders, including a focus on physical activity/strengthening, medication, and psychological/behavioral health.2,11

Hypermobile EDS: How to Manage Chronic Pain with Non-Pharmacologic Modalities

Individualized Exercise Programs

Despite rather lacking clinical evidence, it is generally recommended that physical approaches in prophylactically preventing and treating nociceptive pain involved in hEDS center on improving joint stability and reducing musculoskeletal tightness.2,11,12 Of course, one of the difficulties in not only promoting these programs in this population but having patients consistently engage with them, is that pain, fatigue, and fear of injury are commonly reported barriers to positive exercise and physical activity.12,13

Thus, there is a recognized importance placed on individualizing strength training in each patient with hEDS, involving different exercises and techniques that are gradually incorporated12

Muscle Strength and Resistance Training

Specifically, muscle strength has been shown to help reduce limits in physical activities experienced by people with hEDS. Proprioception is not directly associated with physical limitations in those with hEDS, further supporting an individualized approach to exercise regimens.10 In addition, studies have shown that improving muscle tone (resting state of muscle contraction) through low resistance training, with gradual increases in repetitions can benefit joint stabilization.2,14

Safe Stretching

Stretching exercises should be limited to more gentle forms to avoid potentiation of subluxation or dislocations. Table II provides examples of exercises and trainings that can be tailored to affected areas of the body.

Physical Therapy

Physical therapy offers a potential way for patients with hEDS to engage in physical activity in a targeted and guided manner. However, it is important to ensure that physical therapy performed in patients with hEDS be led by those experienced with this disorder, given reports of increased pain and reduced quality of life with improper exercises.15 PT programs should consist of core stabilization, joint stabilization, and proprioception enhancement, as well as manual therapy for overactive muscles, re-education, and joint mobilization with muscle release.11,12

There is some quality clinical evidence to support physical therapy for hEDS activity in young patients. Kemp et al performed a prospective controlled trial in children aged 7 to 16 with joint hypermobility for 6 weeks with a focus on improving muscular strength and fitness while correcting motion control, and found significant improvements in children and parental pain scores.16 Another study in children aged 7 to 16 years with joint hypermobility found increased psychosocial/self-esteem in a group who performed knee exercises into the hypermobile range of motion (ROM) compared with the control cohort who was limited to the neutral ROM.17

In adults, one controlled trial showed reduced knee pain and increased proprioception in a group receiving targeted exercises of proprioception, balance, and plyometrics compared with a control group receiving no exercises.18

However, the majority of guidance available recommends further research into physical therapy, and physical activity overall, for managing hEDS pain.

Cognitive Behavioral Therapy

Much like other chronic illness and life-dominating disease states, cognitive behavioral therapy (CBT, see also how to administer CBT in primary care) should also be considered a treatment adjunct in patients with hEDS.11 Unfortunately, there have been no clinical trials to date that have evaluated specific forms of CBT in management of hEDS, although there have been case reports noting anecdotal efficacy.19 Considering the prevalence of comorbid mood, sleep, and fatigue disorders, as well as common reports of negative feelings and poor emotional regulation in all types of Ehlers-Danlos Syndrome, CBT approaches are agreed to offer potential benefit.11,20

How to Manage Chronic Pain in hEDS with Pharmacologic Modalities: Medication Options


Similar to the options for non-pharmacologic management of hEDS, clinical evidence supporting the use of pharmacologic modalities is also rather lacking. Due to the potential inflammatory nature of different types of chronic pain in hEDS, NSAIDS are generally recognized as a mainstay form of pharmacologic therapy to reduce inflammation and improve pain.2,11 However, given the wide range of potential toxicities, including gastrointestinal, renal, and cardiovascular, with oral NSAIDS, their use may be limited.


In this respect, topical NSAIDs can offer potential benefit, given the majority of these have low systemic absorption, high joint absorption, and thus good potential to reduce local inflammation. Common commercially available formulations include:

  • diclofenac sodium gels and liquids at various strengths
  • the diclofenac epolamine patch.

Other specialized formulations, which can be compounded at specialty pharmacies, include:

  • ibuprofen
  • ketoprofen
  • indomethacin

Alternative Medications: SNRIs, TCAs, Anti-Convulsants, Muscle Relaxers

Various neuromodulating medications can also offer potential benefit in patients with hEDS who present with neuropathic symptoms, including antidepressants with serotonergic and noradrenergic activity (such as SNRIs and TCAs), and specific anti-convulsants. Again, it is important to consider that there have been no trials to date assessing the effects of these medications on pain in hEDS.2,11

Muscle relaxants can also be used to reduce any underlying spasticity associated with hEDS, although there is a theoretical risk that long-term use can possibly exacerbate joint instability, which also may limit overall use.2

Chronic use of opioids for hEDS are generally considered to be last-line options in terms of recommended pharmacologic treatment modalities, due to the long-term risk of chronic opioid therapy. An exception for short-term opioid use may be for acute pain flare-ups.2,11 2,11 However, if patients fail multiple treatments as aforementioned, opioids can offer a reasonable option in low-risk patients, with appropriate monitoring.2,11


Emerging Treatments for Ehlers-Danlos Syndrome: Naltrexone, Glial Cell Modulators, NGF Inhibitors

Unfortunately, in the realm of future directions of pharmacologic management for Ehlers-Danlos Syndrome, including hypermobile EDS, there do not appear to be specific drugs in clinical development. There has been some mention low dose naltrexone being a potential medication in the treatment of chronic pain associated with hEDS, given its potential role in modulating microglia and “resetting” the endogenous opioid system, thereby potentially reducing neuropathic pain and central sensitization.11,21

Further, given the neuromodulating and anti-inflammatory actions of pipeline glial cell modulators, as well as the anti-inflammatory actions of pipeline nerve growth factor inhibitors, from a mechanistic perspective these medications may be able to provide potential benefits to reduce pain in patients with hEDS; however, further research is absolutely warranted.22,23)

Overall, hEDS is one of the most common subtypes within the EDS spectrum, and yet, it is often misunderstood. Appropriate management of patients with EDS involves the crucial recognition of clinical signs and symptoms, accurate diagnosis, and the optimization of both non-pharmacologic and pharmacologic modalities to best improve chronic pain and associated symptoms. More therapeutic options need to be evaluated with the goal of more effectively managing EDS and the long-term function of patients.

Last updated on: July 7, 2021
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Ehlers-Danlos Syndrome: An Emerging Challenge for Pain Management
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