What pain mechanisms are involved with endometriosis-caused pelvic pain?

What pain mechanisms are involved with endometriosis-caused pelvic pain?

Enhanced understanding of the mechanisms involved with chronic pain in endometriosis is helping pave the way toward new treatment approaches

By Kathleen Krafton

Although it has been more than 100 years since endometriosis was first described in the literature, deciphering the mechanisms that cause many (but not all) women with this enigmatic disease to experience pain is an ongoing pursuit.

Pain is the most debilitating symptom of endometriosis.1,2 In many cases, it has a profoundly negative impact on a patient’s quality of life, and it contributes significantly to disease burden, as well as to personal and societal costs that result from lost productivity.3,4 Women with endometriosis often experience chronic pelvic pain, dyspareunia, dysmenorrhea, and subfertility.5 The majority of women with the disease also have one or more comorbidities, including adenomyosis, adhesive disease, and inflammatory conditions such as interstitial cystitis and inflammatory bowel disease.6-8


Perspectives on Endometriosis Management

In recent years, studies have yielded new insights into the early processes of disease formation, and the role new nerve fiber growth, peritoneal fluid and inflammation, and the central nervous system may play in endometriosis-associated pelvic pain are becoming increasingly clear.5,9,10 These discoveries have important treatment implications.

In this article, Andrea J. Rapkin, MD, Professor of Obstetrics and Gynecology at the University of California, Los Angeles, and Founder and Director of the UCLA Pelvic Pain Center, offers her expert opinion on the findings of key studies and their clinical implications, including the importance of a multidisciplinary treatment approach that focuses on the whole patient.

1. What mechanisms underlie the chronic pain that many women with endometriosis feel?

Although pain is the primary symptom that women with endometriosis present with, disease burden and symptom severity do not always correlate.11,12 “This was the first conundrum presented to clinicians,” noted Dr. Rapkin. “In fact, we don’t know the true prevalence of endometriosis because women with endometriosis only come to diagnosis either based on pain or infertility. When infertility is the problem, very often we are surprised by how much disease is present in an individual with either no pain or minimal pain. Conversely, other individuals with very severe pain, upon laparoscopic surgery, have very little endometriosis.”

Efforts to solve this clinical puzzle began decades ago. “Dr. Michael Vernon discovered that small, red, endometriosis implants that looked like petechiae produced more prostaglandin E2 (PGE2) in vitro, and the PGE2 is an algesic chemical that is produced after cytokines stimulation,” said Dr. Rapkin. “This was the first evidence that, yes, there is a reason for pain in many individuals that we weren’t aware of before.”

“Prostaglandins are known to be the major cause of pain in women with dysmenorrhea. In addition to producing uterine cramping and sensitizing nerve endings, prostaglandins also promote other inflammatory factors that are responsible for attracting monocytes that become macrophages further contributing to inflammation and possibly infertility,” Dr. Rapkin continued. “We also know PGE2 stimulates the enzyme aromatase, which allows androgens to be converted to estrogen. This is a self-feeding aspect of endometriosis.”

These discoveries were followed by the realization that deeply infiltrating endometriosis—with infiltration of more than 5 mm, often in the uterosacral ligaments,—was more likely to be painful than superficial disease, said Dr. Rapkin.

“That’s when we came to think that in some women with endometriosis, the disease we saw laparoscopically was really the tip of the iceberg.”

In 2005, landmark work performed by Karen J. Berkley, PhD, was summarized in a paper coauthored by Dr. Berkley, Dr. Rapkin, and Raymond E. Papka, PhD.13 “In a rodent model where endometriosis was developed by suturing pieces of endometrium in the mesentery, the endometriosis implants developed not only a vascular supply but also a nerve supply. These nerves were not just functioning to govern the dilation and contraction of the blood vessels (in other words the sympathetic type nerves), but they were actually nerves that stained for neurotransmitters associated with pain (algesic agents, such as substance P and CGRP),” said Dr. Rapkin. “At UCLA, we acquired tissues from women with endometriosis and analyzed them in Dr. Papka’s lab. Those tissues also showed the same phenomenon of nerves staining the pain-producing chemicals.” Other studies performed around the world also demonstrated nerve endings with neurotrophic-type chemicals in endometriotic tissues.

2. What other chronic pain conditions might women with endometriosis experience?

Overlapping chronic pain conditions are unfortunately a common phenomenon in women with endometriosis. “It was first established that there is a very high co-occurrence of interstitial cystitis or bladder pain syndrome,” said Dr. Rapkin. “ Irritable bowel syndrome is more common in women with endometriosis, as is vulvodynia. Fibromyalgia, migraine headache, temporo-mandibular joint pain (TMJ), anxiety, and depression also commonly co-occur in women with endometriosis.”

“Two concepts may be relevant to why these overlapping pain conditions develop,” Dr. Rapkin continued. “First, visceral sensitization: If one organ is hyperalgesic then other organs in the adjacent region or dermatome can become sensitized, through shared cell bodies in the spinal cord, cross-sensitization in the cord or at at higher regions of the CNS. In addition, visceral somatic conversion occurs, whereby somatic tissues with the same nerve supply as the affected organs become sensitized. This process may explain why abdominal wall and pelvic floor muscles get in on the act. The involvement of surrounding musculature is an important part of the pain production in endometriosis.”

“Finally, genetic studies of alterations in genes that encode for receptors affecting the sensitivity and perception of pain are shedding light on the development of chronic pain.”

“Ultimately these studies will advance our understanding of pain related to endometriosis.”

The summary diagram shows some of the many factors that influence pain. The red box shows processes that occur in the periphery. Nerve growth factor (NGF) and other inflammatory mediators are increased in the peritoneal fluid (PF). These have an action on the nerves in the periphery, for example, sensitization. There is also evidence for increase in nerve growth in the periphery. The black boxes in the diagram represent an unknown mechanism(s). For example, we do not yet understand how increased growth of neurites in the periphery has an effect on the pain perception, but there is evidence that it does. Similarly, there is an unknown mechanism by which PF influences the pain perception. The surgical knife in the periphery represents the go-to method of treatment of endometriosis-associated pain and also shows how damage to the nerves can occur as a result, which may lead to increased pain. The green arrow represents ascending modulation of pain and the blue arrow represents the descending modulation of pain, which have been shown to be disrupted in patients with chronic pain. The external factors are represented, such as mood, as well as other biological factors (ie, genetics), which are known to influence the pain experience. Both mood and stress has an effect on the HPA axis, which presents during changes in cortisol levels, which may also affect pain perception.9

3. How have new understandings about the pain mechanisms involved with endometriosis-caused pelvic pain improved treatment of the disease?

According to Dr. Rapkin, the increased understanding of the mechanisms involved in endometriosis-associated pain gained from these key studies led to a paradigm shift, with endometriosis being viewed not just as a condition with mechanical hypersensitivity due to altered anatomy and inflammation but also as a neurologic condition, or a nerve pain condition with peripheral and central sensitization. “This means there is upregulation or hyperactivity both in the periphery (in the pelvis) and centrally (in the spinal cord and brain),” said Dr. Rapkin.

“In the periphery, if the endometriotic lesions become innervated, they develop an afferent sensory innervation, and communicate with the brain. Stimulation of these nerves by the inflammatory milieu then causes pain,” she continued. “Along these lines, in addition to prostaglandins and cytokines, there is increased expression of various neuropeptides, neurotrophins, and ion channels that contribute to hypersensitivity and pain.”

Dr. Rapkin noted research by Maria Adele Giamberardino that showed women with endometriosis and pain have a lower threshold for feeling sensation in the tissues overlying the pelvis (the abdominal wall and back),14 which also has been shown by Dr. Berkley in animal models.15

“Women with severe endometriosis and severe menstrual pain have also been shown to have a lower threshold for sensing electrical stimulation of the abdominal wall muscle,” said Dr. Rapkin.

“The muscle starts to develop trigger points or tender hyperalgesic points. This is part of the sensitization process. In addition, other studies demonstrated distant sensitization—women with pelvic pain and endometriosis have a lower threshold for sensing experimental pain in areas outside the pelvis, for example the back, leg, or shoulder. These discoveries clearly reflect up regulation in the central nervous system.”

Dr. Rapkin also pointed to research published in 2016 by Sawson As-Sanie, MD, MPH, that showed an association between endometriosis-associated pelvic pain and altered brain chemistry and function.16 “Dr. As-Sanie demonstrated a decrease in gray matter volume in key neural pain processing areas in the brain in women with pain with endometriosis. This was not found in women with endometriosis who did not have pain,” she said. “Altered connectivity in brain areas related to perception and inhibition of pain is important in maintaining pain, and Dr. As-Sanie’s studies also found that these changes are correlated with anxiety, depression, and pain intensity in patients with endometriosis and chronic pain.”

4. What are some newer treatment approaches to chronic pain with endometriosis?

“Multidisciplinary approaches to endometriosis-related pain are important,” said Dr. Rapkin. “Although it’s important to excise or cauterize endometriosis lesions, or debulk as much as can safely be removed during laparoscopic surgery, it is now standard of care that surgery should not in fact be the first approach to treatment. Endometriosis is a chronic condition. Inflammatory factors will continue to play a role in patients who continue to ovulate and menstruate. So instead of just focusing on surgery, we want to decrease levels of reproductive hormones that contribute to the disease. We want to suppress reproductive hormones in a way that is compatible with long-term quality of life for our patients. Wiping out estrogen and placing patients into a chemical menopause for most of their reproductive years is not desirable.”

Approaches to hormonally modulate endometriosis include combined hormonal contraceptives and progestin-only medications, such as the levonogestrol-containing IUD, progestin-containing contraceptive implants, injections, or tablets. These may not provide sufficient pain relief for some patients. “There is some evidence from Dr. Giamberadino that after women had been treated with oral contraceptives, the abdominal wall hyperalgesia decreased,” said Dr. Rapkin. “The question is, why don’t we see this in all patients? We come to the realization that endometriosis has to be treated as a neurologically mediated disorder. We have to treat it in a multidisciplinary way.”

A holistic approach to endometriosis is a new and exciting area for the field, said Dr. Rapkin. “We have to treat ‘bottom-up’, and ‘top-down.’ Bottom-up means we are addressing the peripheral factors that contribute to pain: endometriotic lesions, other pelvic organ pain, while also addressing the trigger points, the tender points, the muscle dysfunction in the abdominal wall, the back, the pelvic floor. There are now many pelvic floor physical therapists who can help women with pain and endometriosis. Often, women with endometriosis have myofascial pain and pain related to the other comorbid pain conditions they may have developed. Pain can be augmented by their cognitions and beliefs about pain, anxiety and depression. So the top-down approach addresses the cognitions, depression, and anxiety.”

“We don’t consider endometriosis a psychosomatic condition, but we know that if you don’t address the central upregulation, including anxiety and depression, we may not get anywhere.”

“Interestingly, the same neurotransmitters governing mood often have to do with nerve pain. Increasing serotonin, norepinephrine, binding calcium channels by exploring the use of gabapentin may prove fruitful. Cognitive behavioral therapy is another approach—to stimulate the prefrontal cortex, the area that’s involved in pain inhibition, and other areas of the brain that may produce endogenous opioids to help with inhibiting pain. Bringing in complementary approaches is very important. For example, mindfulness-based meditation or yoga. There’s growing evidence for acupuncture as well. Physical therapists, pain psychologists, anesthesiologists, or gynecologists who are facile with nerve blocks, to help tone down hyperalgesic tissues, in addition to medical and surgical therapy, have the possibility of really improving the lives of women with endometriosis.”

5. What key pearls would you like to share with readers?

We closed by asking Dr. Rapkin to reflect on key takeaways for clinicians. “It’s important to evaluate the entire individual,” she said. “Don’t just viscerally focus on the uterus, the ovaries, fallopian tubes, and the peritoneum—investigate the adjacent and distant somatic tissues. Think about the abdominal wall, think about the pelvic floor. Learn how to evaluate these structures. There are simple evaluation techniques that gynecologists can learn and should include with every patient with pelvic pain, whether or not they are suspected of having endometriosis.”

“You also want to get a broad history. Find out if there are other overlapping pain conditions—if so, that’s already a sign that there may be central sensitization.”

“Very often, it’s necessary to bring in a pain psychologist. Not for psychotherapy and not because the disease is psychosomatic, but to help the patient to learn how to inhibit pain signals, to use their brain to erase pain memory, and of course to address the concomitant anxiety, depression, and social isolation that happens with pain.”


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Dr. Rapkin reports no financial relationships relevant to this article.
Kathleen Krafton is a contributing writer for OBG Management.