Central sensitization: The pain point isn’t always the pelvis

Text by Kari Oakes

Video by M. Alexander Otto

Why is there so often a discrepancy between the severity of symptoms in endometriosis and the disease burden that surgeons find? Why does pain persist for many women, despite aggressive surgical treatment of lesions? Why are symptoms sometimes exacerbated by non-noxious situational stimuli such as tight clothing and even a bright or noisy environment?

 

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Appreciation of the role of central sensitization for women with endometriosis may go a long way toward solving many of these puzzles, Katy Vincent, MBBS, DPhil, said at the 13th World Congress on Endometriosis in Vancouver.

Increasingly, central sensitization is being seen as a contributor to all sorts of chronic pain conditions. In the face of persistent nociceptive stimuli, central processing of nonpainful afferent signals can eventually “jump the track” and be processed through afferent pain pathways, causing nonpainful stimuli to be perceived as pain. Once this pathway is activated, neurotransmitters are upregulated, excitatory signaling escalates, and a positive feedback loop is initiated that can lock patients into a cycle of pain, even after the initial noxious stimulus is gone.

Katy Vincent, MBBS, DPhil


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Once thought to be primarily active in such chronic pain syndromes as fibromyalgia and irritable bowel syndrome, central sensitization may play a role in other conditions, including osteoarthritis and even acute postsurgical pain.

Reviewing what’s known about pain processing in endometriosis, Dr. Vincent, of the department of obstetrics and gynecology at the University of Oxford, England, laid out a framework for studying endometriosis that moves beyond the pelvis to take the whole person into account. Her work is part of her participation in Oxford’s Endometriosis Care and Research Centre.

“So, this is an area where I think the evidence is increasing,” though sample sizes are still small, Dr. Vincent said in an interview. “We know that, in all chronic pain conditions that have been studied, central processing of peripheral stimuli is amplified,” and this effect is also seen in endometriosis, she said.


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Once thought to be primarily active in such chronic pain syndromes as fibromyalgia and irritable bowel syndrome, central sensitization may play a role in other conditions, including osteoarthritis and even acute postsurgical pain.

Reviewing what’s known about pain processing in endometriosis, Dr. Vincent, of the department of obstetrics and gynecology at the University of Oxford, England, laid out a framework for studying endometriosis that moves beyond the pelvis to take the whole person into account. Her work is part of her participation in Oxford’s Endometriosis Care and Research Centre.

“So, this is an area where I think the evidence is increasing,” though sample sizes are still small, Dr. Vincent said in an interview. “We know that, in all chronic pain conditions that have been studied, central processing of peripheral stimuli is amplified,” and this effect is also seen in endometriosis, she said.

Clues from the patient

When should central sensitization be suspected? Sometimes, clinicians can be tipped off by a careful history and the language their patients choose when talking about their pain. Patients may describe their pain with words like “burning,” “stabbing,” or “shooting,” offering a clue that nerve-related pain may be a component, Dr. Vincent said.

Additional clues, she said, can be seen in the physical examination of many endometriosis patients. “Even if we just brush the skin lightly or use a cotton tip, for example, you get a very sensitive unpleasant sensation in response to that. That’s not normal, and it can be a marker to us that there may be some central changes going on.”

Dr. Vincent said she suspects that the maladaptive positive feedback loop that misinterprets non-nociceptive input as pain, is, for many patients, a significant factor in their ongoing struggle with endometriosis pain. Until the central component is addressed, the pain will continue.

“The reason that they’re not getting better is that we’re not targeting the central nervous system,” she said.

The pain that these patients are experiencing is real and indistinguishable from pain that’s appropriately induced by nociceptive afferent stimuli. “Believe your patient,” Dr. Vincent said. “There is still a lot we don’t know.”

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“The reason that they’re not getting better is that we’re not targeting the central nervous system,” she said.

The pain that these patients are experiencing is real and indistinguishable from pain that’s appropriately induced by nociceptive afferent stimuli. “Believe your patient,” Dr. Vincent said. “There is still a lot we don’t know.”

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Exploring the unknown

What triggers central sensitization in one endometriosis patient but not another, is one of those unknowns, though the broader body of pain medicine offers some clues.

Many endometriosis patients have had multiple surgeries, and these procedures may themselves introduce the potential for pain sensitization. Clifford Woolf, MD, PhD, whose work initially proposed the mechanisms for central sensitization in chronic pain, noted in a review article that central sensitization plays a part in both postsurgical pain and a variety of visceral pain sensitivity syndromes (Pain. 2011 Mar;152[3 Suppl]:S2-15).

These syndromes, which can be seen in all compartments of the torso, including the chest, abdomen, and pelvis, include noncardiac chest pain, irritable bowel syndrome, chronic prostatitis, and endometriosis. When the review article was published in 2011, Dr. Woolf, who is a professor of neurology at Harvard Medical School, Boston, commented that, with regard to pain syndromes of the urological tract, “not much data is available and few studies have been performed.”

Dr. Vincent and her colleagues at the University of Oxford are working to change that by conducting research into the role that central processing plays in chronic pelvic pain (CPP) and endometriosis. “More recently, we’ve seen some brain imaging studies suggesting that there is some altered processing that more strongly supports this,” she said.

Neuroimaging points the way to early treatment

At the World Congress on Endometriosis, Dr. Vincent and her coauthors presented the results of functional magnetic resonance imaging (fMRI) studies of women with CPP. The 26 women who participated in the study all had CPP and were about to undergo their first laparoscopic procedure.

Participants completed a detailed questionnaire about the quality, severity, and duration of their physical and psychological symptoms. Then, they underwent an fMRI scan that included a resting state sequence. Using previous studies that have identified alterations in brain structure, function, or connectivity in dysmenorrhea, endometriosis, and CPP, the investigators looked for correlations between questionnaire results and fMRI data.

They found a strong correlation between pain duration and functional connectivity between the hippocampus and the periaqueductal gray (PAG; r = 0.599; P = .001). These are two areas of the brain known to be involved in memory consolidation and descending control of pain, respectively. “Duration of pain was logarithmically related to functional connectivity … with the x-intercept at 24 months,” they said, so they divided the participants into those who reported pain for more than 24 months (n = 14) and those whose pain had lasted 24 months or less (n = 12).

The two groups were similar in age, and they reported similar intensity of pain. However, the group with the longer pain duration reported much more depression and anxiety and reported more catastrophization about their pain (depression, P = .0144; state anxiety, P = .0160; trait anxiety, P = .0051; pain catastrophizing, P = .0239).

“At least some of the central changes associated with CPP appear to occur relatively soon after the pain commences, being well-established once pain has been present for 2 years,” Dr. Vincent and her coauthors wrote in the abstract prepared for the presentation.

They found a strong correlation between pain duration and functional connectivity between the hippocampus and the periaqueductal gray (PAG; r = 0.599; P = .001). These are two areas of the brain known to be involved in memory consolidation and descending control of pain, respectively. “Duration of pain was logarithmically related to functional connectivity … with the x-intercept at 24 months,” they said, so they divided the participants into those who reported pain for more than 24 months (n = 14) and those whose pain had lasted 24 months or less (n = 12).

The two groups were similar in age, and they reported similar intensity of pain. However, the group with the longer pain duration reported much more depression and anxiety and reported more catastrophization about their pain (depression, P = .0144; state anxiety, P = .0160; trait anxiety, P = .0051; pain catastrophizing, P = .0239).

“At least some of the central changes associated with CPP appear to occur relatively soon after the pain commences, being well-established once pain has been present for 2 years,” Dr. Vincent and her coauthors wrote in the abstract prepared for the presentation.

Dr. Vincent is likely on the right path, said Tim Salomons, PhD, a neuroscientist and pain researcher at the University of Reading, England, where he directs the Centre for Integrative Neuroscience and Neurodynamics Pain Laboratory.

“My take is that this is right on the money,” he said in an interview. “We know that, for patients with chronic pain conditions, pain is associated with central sensitization. In many cases, we know very little about the drivers of these conditions, so better understanding the central contribution might give us a new way to approach these disorders. In particular, understanding how central sensitization might contribute to the development of chronic pain could help us understand why some people develop chronic pain and might help us intervene before this happens.”

Dr. Salomons also pointed out that the initial transition to central sensitization often occurs in the context of negative affect.

 

Tim Salomons, PhD

A role for cognitive therapies?

Is there the potential for some cognitive control of these pathways? Dr. Salomon’s early work suggests that the answer is yes.

Dr. Salomons, whose work has focused on the intersection between emotion and cognition in how people experience and cope with pain, worked with colleagues to construct an experiment to test this hypothesis. Participants were first given a pain stimulus that is known to provoke secondary hyperalgesia. After their first pain exposure, the subjects – all healthy volunteers – participated in a brief cognitive-behavioral intervention. The single intervention significantly reduced the amount of secondary hyperalgesia participants experienced (Pain. 2014 Aug;155[8]:1446-52).

Further studies are helping physicians and researchers come to a better understanding of how cognitive training can help interrupt this malevolent feedback loop. In a later study, Dr. Salomons found that cognitive behavioral therapy, which he and his coinvestigators implemented in participants who were subjected to the hyperalgesia-inducing pain stimulus, reversed the effect of pain exposure on the neural network involved in pain processing (Pain. 2016 Sep;157[9]:1895-904).

“We noticed that [cognitive behavioral therapy] resulted in a number of functional connectivity changes over the course of the study,” Dr. Salomons said.

Dr. Salomons, whose work has focused on the intersection between emotion and cognition in how people experience and cope with pain, worked with colleagues to construct an experiment to test this hypothesis. Participants were first given a pain stimulus that is known to provoke secondary hyperalgesia. After their first pain exposure, the subjects – all healthy volunteers – participated in a brief cognitive-behavioral intervention. The single intervention significantly reduced the amount of secondary hyperalgesia participants experienced (Pain. 2014 Aug;155[8]:1446-52).

Further studies are helping physicians and researchers come to a better understanding of how cognitive training can help interrupt this malevolent feedback loop. In a later study, Dr. Salomons found that cognitive behavioral therapy, which he and his coinvestigators implemented in participants who were subjected to the hyperalgesia-inducing pain stimulus, reversed the effect of pain exposure on the neural network involved in pain processing (Pain. 2016 Sep;157[9]:1895-904).

“We noticed that [cognitive behavioral therapy] resulted in a number of functional connectivity changes over the course of the study,” Dr. Salomons said.

Clinical implications

Better understanding of these mechanisms could have real clinical implications. “We’re starting to see longitudinal imaging papers that are finding predictors of the development of chronic pain, as well as some of the changes that occur as that happens,” Dr. Salomons said. “So, in my opinion, we’re getting close to the point where we can start to understand the brain’s role in the development, and hopefully treatment, of chronic pain. I think examining central sensitization within this context is going to be critical.”

 

 

Dr. Vincent and Dr. Salomons are contemplating a collaboration to use neuroimaging to elucidate further the role that central sensitization plays in some women’s endometriosis symptoms and to explore cognitive-behavioral approaches for these patients. Dr. Vincent emphasized, however, that psychological distress is not the underlying cause of the pain.

“The tricky part of doing this is disentangling the central and peripheral contributions, as it can be very hard to know whether observed sensitization is driven by the brain/spinal cord or is due to peripheral factors we aren’t detecting,” she said

“So, I think this is one area where neuroimaging might be helpful. Imaging might also help us understand how central sensitization is affected by cognitive and emotional factors.”

Dr. Vincent reported research funding from Bayer and Pfizer, and lecture fees from Bayer Grunenthal and Gedeon Richter. Dr. Salomons reported having no relevant financial disclosures.

Kari Oakes and M. Alexander Otto are writers for Ob.Gyn. News.

 

Dr. Vincent and Dr. Salomons are contemplating a collaboration to use neuroimaging to elucidate further the role that central sensitization plays in some women’s endometriosis symptoms and to explore cognitive-behavioral approaches for these patients. Dr. Vincent emphasized, however, that psychological distress is not the underlying cause of the pain.

“The tricky part of doing this is disentangling the central and peripheral contributions, as it can be very hard to know whether observed sensitization is driven by the brain/spinal cord or is due to peripheral factors we aren’t detecting,” she said

“So, I think this is one area where neuroimaging might be helpful. Imaging might also help us understand how central sensitization is affected by cognitive and emotional factors.”

Dr. Vincent reported research funding from Bayer and Pfizer, and lecture fees from Bayer Grunenthal and Gedeon Richter. Dr. Salomons reported having no relevant financial disclosures.

Kari Oakes and M. Alexander Otto are writers for Ob.Gyn. News.