hEDS-related Pain May Be Linked to Deficit in Pain Control Mechanisms, Study Shows

hEDS-related Pain May Be Linked to Deficit in Pain Control Mechanisms, Study Shows
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Pain in people with hypermobile Ehlers-Danlos syndrome (hEDS) likely is the result of an impaired pain suppression system that may lead to widespread pain, a study shows.

The data, which also contradict a previous theory that EDS-related pain was caused by damage in nerve fibers, may help in the development and identification of effective therapies to manage pain in these patients.

The study, “Pain due to Ehlers-Danlos Syndrome Is Associated with Deficit of the Endogenous Pain Inhibitory Control,” was published in the journal Pain Medicine.

Pain is a common and serious symptom among hEDS patients. It usually is widespread and associated with fatigue, sleep disturbances, and mood disorders. This suggests that hEDS may be related to a dysfunction in the central nervous system (the brain and spinal cord).

In agreement, a previous study showed that people with hEDS-related pain have signs of central sensitization — defined by lower pain thresholds, resulting in hypersensitivity to pain and maintenance of pain even in situations without harmful stimuli.

This led to the hypothesis that hEDS-related pain is caused by an impaired pain suppression system. However, another study raised the possibility that this pain may be associated with small-fiber neuropathy.

Small-fiber neuropathy is characterized by damage in the small sensory nerves in the skin (small fibers), which can lead to unusual sensations such as pins-and-needles, pricks, tingling, numbness, and burning.

Thus, the underlying mechanisms of hEDS-related pain remain controversial, and clarifying this may help to identify and develop more appropriate approaches to manage pain in these patients.

Now, researchers at the Sapienza University, in Rome, Italy, investigated which of the two theories better reflect the nature of the pain felt by hEDS patients.

They evaluated the function of small fibers and the pain suppression system in 22 people — 21 women and one man — with hEDS-related pain, and in 22 age- and sex-matched healthy individuals.

Patients had a mean age of 43 years and had been diagnosed with hEDS for a mean of 5.5 years.

Small-fiber function was measured through quantitative sensory testing, which uses standardized mechanical and thermal (cold and heat) stimuli to evaluate a person’s detection and pain thresholds, as well as the wind-up effect — when repetitive stimulus increases the pain intensity. A higher wind-up effect is a sign of central sensitization.

The function of the pain suppression system was assessed using the conditioned pain modulation test, which relies on the concept that one stimulus can naturally override another, creating the so-called “pain-inhibits-pain” effect.

This test essentially involved having a prolonged pain-inducing heat stimulus (conditioning stimulus) applied to the participant’s dominant forearm and measuring how this overrode a similar, but shorter, pain-inducing heat stimulus (test stimulus) applied to the participant’s non-dominant forearm.

A reduction in the rating of the test stimulus during conditioning indicates an intact pain suppressing system, while an increase in the test stimulus rating suggests problems in this system.

Results showed that while some patients complained of pain mainly involving the joints, most reported widespread pain, described as a combination of burning, dull, and aching sensations.

“This finding indicates that hEDS-related pain does not merely reflect joint abnormalities such as luxation and dislocation, but manifests as widespread pain,” the researchers wrote.

In addition, hEDS patients showed no signs of small-fiber damage or pain associated with nerve cell dysfunction (neuropathic pain). In contrast, they had a significantly higher wind-up effect than healthy individuals, suggesting the presence of central sensitization.

This is in agreement with previous studies demonstrating that people with hEDS have higher sensitivity to mechanical and thermal stimulation, the researchers noted.

Notably, hEDS patients did show lower cold and heat pain thresholds, compared with healthy participants. However, these differences were not statistically significant, which may be due to the relatively small sample size, the team observed.

Moreover, hEDS patients showed an increase in the rating of the test stimulus during conditioning, suggesting they have an impaired pain suppression system.

Taken together, the findings indicate that hEDS-related pain may not be associated with small-fiber damage, but with central sensitization, possibly due to problems in the pain suppression system.

The data “showed that in virtually all patients with hEDS- related pain small-fiber function is preserved. Conversely, … these patients have a deficit of the descending inhibitory pain control,” researchers wrote.

They hypothesized that in the initial phases of the disease, pain may be mainly caused by joint hypermobility complications, and that such persistent pain may subsequently promote central sensitization and changes in the pain suppression/inhibitory system.

Researchers emphasized, however, that further studies using several methods to assess small-fiber damage are needed to confirm there is indeed no such damage in these patients.

Also, medications restoring the pain suppression system, such as antidepressants, “might be effective for reducing pain in this condition,” the researchers wrote, adding that more clinical studies are needed to confirm this hypothesis.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.
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Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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