Background
Brief overview of possible pain contributors in endometriosis
Nociceptive contributors
Inflammation and peripheral sensitization
Central sensitization and chronic overlapping pain conditions (COPCs)
Myofascial contributors
Psychological contributors
Management of pain contributors in endometriosis
Treatment of nociceptive pain
Reduction of inflammation
Treatment of central sensitization
Assessment of other COPCs and their treatment
Treatment of myofascial pain
Psychological screening and treatment
Conclusions
AUTHOR, YEAR | JOURNAL | OBJECTIVE | STUDY TYPE | RESULTS |
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Nociceptive pain contributors
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Tokushige et al., 2006 | Hum. Reprod. | To compare the innervation of peritoneal endometriotic tissue collected from 40 women with endometriosis with the peritoneum of 36 healthy women | Observational study | Peritoneal endometriotic lesions are innervated by sensory A-delta, sensory C, cholinergic and adrenergic nerve fibres. There were more nerve fibres identified in peritoneal endometriotic lesions than in normal peritoneum or endosalpingiosis lesions. |
Gruber et al., 2021 | Cells | To describe the pathogenesis of endometriosis, pain development and subfertility | Narrative review | Peritoneal endometriotic lesions show a hyperinnervation of sensory nerve fibers and a loss of sympathetic nerve fibers. An imbalance in the release of pro-inflammatory and anti-inflammatory sympathetic neurotransmitters seems to occur, resulting in neurogenic inflammation. |
Anaf et al., 2011 | Gynecol. Obstet. Invest. | To analyze the nerve density in deep infiltrating endometriotic nodules of the posterior vagina and in the adjacent healthy vaginal tissue | Prospective study | An increased number of nerve structures in endometriotic nodules may contribute to the severe neuropathic pain that characterizes these lesions. |
Vercellini, 1997 | Semin. Reprod. Endocrinol. | To describe pain in endometriosis | Narrative review | The specific characteristics of the lesions are more implicated in the genesis of pain than disease extension. Intraperitoneal implants may cause functional pain symptoms, whereas infiltrating lesions are responsible for organic-type pain. |
Porpora et al., 1999 | J. Am. Assoc. Gynecol. Laparosc. | To evaluate the relationship between prevalence and severity of CPP and stage, site, and type of endometriosis | Prospective observational study | Deep endometriosis, pelvic adhesions and ovarian cystic endometriosis were independent predictors of pelvic pain. It is not the size of ovarian cystic endometriosis but the association with adhesions that causes pelvic pain. |
Inflammation and peripheral sensitization
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Taylor et al., 2021 | Lancet | To provide an overview of endometriosis as a systemic disease | Narrative review | Endometriosis is a systemic inflammatory disease; proinflammatory cytokines and shifts in circulating immune cell populations create an inflammatory environment extending outside the pelvis. |
Suryawanshi et al., 2014 | Clin. Cancer. Res. | To provide a comprehensive analysis of immune gene expression in in endometriosis and EAOC | Case-control study | One third of patients with endometriosis revealed a tumor-like inflammation profile, suggesting that cancer-like immune signatures may develop earlier, in patients classified as clinically benign. |
Zhang et al., 2018 | Autoimmun. Rev. | To review the current understanding between autoimmunity and endometriosis | Narrative review | Changes in the immune response have been reported in women with endometriosis. Female and hormonal predominance, genetic polymorphisms, immunological abnormalities and chronic conditions are aspects in common with autoimmune diseases. |
Lin et al., 2006 | Endocrinology | To investigate the role of inflammatory cytokines, immune cells, and angiogenesis in the development of endometriosis in a mouse model | Animal study | The implantation of ectopic uterine tissue in the peritoneal cavity of a mouse model induced an inflammatory response. Neutrophils and macrophages are recruited and activated, producing VEGF and leading to angiogenesis in the ectopic tissue. |
Klein et al., 1993 | Am. J. Reprod. Immunol. | To assess whether resident leukocytes in endometriosis express IFN-γ mRNA and to compare this expression to that of normal endometrium | Case-control study | The overall concentration of T cells and macrophages expressing IFN-γ mRNA is significantly greater in endometriotic lesions as compared to the eutopic endometrium. |
Symons et al., 2018 | Trends. Mol. Med. | To provide in-depth insights into current understanding of the immunopathophysiology of endometriosis and highlight challenges and opportunities for future research | Narrative review | Immunological dysfunction facilitates the growth of endometriotic lesions and perpetuates disease symptoms. Targeting dysregulated immune pathways represents a potential avenue for novel therapeutic development. |
Slabe et al., 2013 | Geburtshilfe Frauenheilkd | To compare peripheral blood lymphocyte subpopulations during the menstrual cycle between women with peritoneal and ovarian endometriosis and healthy controls | Case-control study | The concentration of cytotoxic and activated lymphocytes did not fluctuate during the menstrual cycle in women with endometriosis. A marked increase in the concentration of regulatory T cells was detected in the luteal phase. |
Chuang et al., 2015 | Journal of Pathology | To evaluate potential mechanisms of immune dysfunction during endometriosis development analysing peritoneal macrophages of women with endometriosis | Case-control study | In endometriosis the phagocytic ability of endometriotic peritoneal macrophages is impaired. |
Greaves et al., 2015 | Am. J. Pathol. | To determine the role of estradiol in the regulation of the interaction between macrophages and nerves in peritoneal endometriosis using human tissues and a mouse model of endometriosis | Randomized controlled trial | Estrogens play a pivotal role in cross talk between neurons and macrophages. Estrogens act on nerve fibers to enhance the expression of CSF1 and CCL-2, recruiting macrophages to nerve fibers. They also act on macrophages to enhance expression of BDNF and NT-3, which further potentiates neurogenesis in endometriotic lesions. |
Wu et al., 2017 | J. Neuroinflammation | To describe the macrophage and nerve interaction in endometriosis | Narrative review | Retrograde menstruation promotes an inflammatory microenvironment, macrophage infiltration and hyperinnervation. Macrophages migrate into the endometriotic lesions. Within the lesions they secrete proteins that have neuroprotective properties, promoting the outgrowth of nerve fibers. |
Giacomini et al., 2021 | Int. J. Mol. Sci. | To provide an overview of the intersection between inflammation and genetics in endometriosis | Narrative review | The MAPK and the WNT/β-catenin cascades are signalling pathways that have been suggested to interfere with the establishment of endometriosis via several mechanisms, including apoptosis, migration and angiogenesis. |
Lang et al., 2014 | Exp. Neurol. | To describe the role of axon regeneration regulation during neuroinflammation | Narrative review | Axon regeneration regulators play a role in neuroinflammation. |
Arnold et al., 2012 | Brain. Behav. Immun. | To investigate possible pain mechanisms in patients with peritoneal endometriosis | Case-control study | The imbalance between sympathetic and sensory nerve fibres in peritoneal endometriosis might be involved in the maintenance of inflammation and pain. |
Miller et al., 2015 | Womens’ Health | To describe the role of alterations of pelvic innervation in women with endometriosis | Narrative review | The density of sensory C and sensory A-delta sympathetic and parasympathetic nerve fibers is increased in endometriotic lesions. There is a close histological relationship between endometriosis and mast cells, which play an important role in the pathogenesis of many types of chronic pain. |
As-Sanie et al., 2019 | Am. J. Obstet. Gynecol. | To review current practice, describe the barriers affecting diagnosis and treatment, and highlight research priorities for the future of endometriosis care | Narrative review | There is only a marginal relationship between number of lesions, severity of disease, symptoms, and overall impact on quality of life. Comprehensive and interdisciplinary approaches that take patients’ holistic needs into account are needed. |
Central sensitization and COPCs
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Ren et al., 2007 | Mol. Neurobiol. | To describe the role of BDNF-TrkB signaling and NMDA receptors in pain facilitation and activity-dependent plasticity in pain modulation | Narrative review | Pain modulatory circuitry in the brainstem exhibits considerable plasticity in response to injury. The synaptic plasticity observed in the pain pathways shares many similarities with other forms of synaptic plasticity. |
Nijs et al., 2021 | J. Clin. Med. | To povide an overview on past and present IASP criteria for nociplastic pain | Narrative review | In 2017, the IASP introduced the term “nociplastic pain” as a third mechanistic pain descriptor in addition to nociceptive and neuropathic pain, providing a label to patients having a predominant central sensitization type of pain. |
Till et al., 2022 | Obstet. Gynecol. Clin. North. Am. | To review individual COPCs, risk factors and common mechanisms. To review evaluation and communication strategies to establish a productive therapeutic relationship | Narrative review | Patients with co-occurring COPCs may benefit from the addition of treatments aimed at central sensitization, including pharmacologic and non-pharmacologic strategies. An interdisciplinary approach is essential, as no single provider has adequate expertise to manage all these conditions alone. |
Raimondo et al., 2022 | J. Minim. Invasive. Gynecol. | To assess the prevalence of CS and its association with demographic and clinical factors in patients with endometriosis | Cross-sectional study | The prevalence of CS was 41.4% among patients with endometriosis. Moderate-to-severe pain symptoms were significantly more frequent in the CS group, except for dyschezia. |
Orr et al., 2022 | Pain | To identify a CSI cut-off in the endometriosis population to discriminate individuals with significant central pain contributors | Cross-sectional study | A CSI score > 40 may identify patients with endometriosis with pain contributors related to CS. A significant correlation between an increasing score of CSS and increasing pain scores was observed. |
Marchand, 2008 | Rheum. Dis. Clin. North. Am. | To describe the physiology of pain mechanisms | Narrative review | Keeping in mind the heterogeneity of pain responses and the unique characteristics of individual patients leads to better patient care. A greater understanding of the neurophysiologic mechanisms underlying the development and maintenance of pain could prove useful to reinforce inhibitory mechanisms or reduce the hyperactivity of the nociceptive response. |
Ezra et al., 2019 | Front Psychiatry | To describe the Four-Cluster Spectrum of Mind-Body Interrelationships | Narrative review | Diseases may be classified in four clusters in which the mind-body ratio is progressively increasing (cluster 1: organic conditions; cluster 2: stress-exacerbated, typically inflammatory diseases; cluster 3: functional somatic syndromes; cluster 4: conversion disorders). |
Morotti et al., 2017 | Eur. J. Obstet. Gynecol. Reprod. Biol. | To describe mechanism of pain in endometriosis | Narrative review | Endometriosis-associated pain is similar to that of other chronic pain conditions in its engagement and alteration of the CNS. |
Green et al., 2022 | Clin. Obstet. Gynecol. | To provide a systematic approach to persistent pain in patients with endometriosis | Narrative review | Treatment of chronic pain is best achieved by addressing both peripheral and central components of pain. A combination of mind-body and interdisciplinary interventions is recommended as well as surgery and single-agent pharmacotherapy. |
Myofascial contributors
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Ross et al., 2021 | J. Midwifery Womens Health | To describe the presence of myofascial pelvic pain in chronic pelvic pain syndromes | Narrative review | Myofascial pain may be the missing piece when conventional treatments fail to completely relieve patient’s discomfort. Several myofascial pain therapies are low-intervention and significantly enhance patients’ quality of life. |
Aredo et al., 2017 | Semin. Reprod. Med. | To provide a background to understand how endometriosis facilitates remodeling of neural networks, contributing to sensitization and to the generation of MTrPs | Narrative review | Over time, CS creates a process for pain sustention that is independent of the initial pathology and is potentially reversible. Viscerosomatic convergence may not only provide the means for pain referral to somatic structures but also govern the reflex that induces muscle spasm and the formation of MTrPs. |
Phan et al., 2021 | Eur. J. Pain. | To characterize the presence and distribution of pain, myofascial dysfunction and sensitisation beyond the pelvis in women with endometriosis-associated chronic pelvic pain | Cross-sectional study | Women with endometriosis-related chronic pelvic pain may frequently present with myofascial dysfunction and sensitization outside of the pelvic area, which could be caused or sustained by persistent pelvic floor spasm. |
Psychological contributors
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Koller et al., 2023 | JAMA NEtw. Open | To investigate whether pleiotropy contributes to the association of endometriosis with depression, anxiety, and eating disorders | Retrospective study | Endometriosis affects women’s mental health through pleiotropic processes. There is genetic and phenotypic proof of the mechanisms underlying the psychiatric comorbidities of endometriosis. |
Chen et al., 2016 | J. Affect. Disord. | To investigate the temporal association between endometriosis and depression or anxiety disorders | Longitudinal study | Compared to women without endometriosis, affected women are more likely to experience major depressive disorders and anxiety disorders in later life. |
Maulitz et al., 2022 | Front. Neuroendocrinol. | To analyze studies reporting comorbid mental disorders in endometriosis based on the ICD/DSM criteria in the context of available neuroimaging studies | Narrative review | Depression, anxiety, bipolar disorder, alcohol/drug dependency and hyperactivity disorder are all more prevalent in women with endometriosis. This may be explained by pain, presence of comorbidities, inflammation, hormonal treatment, genetic predisposition. |
Doney et al., 2022 | Eur. J. Neurosci. | To provide an overview of inflammation-related mechanisms involved in mood regulation and stress responses on animal models. | Narrative review | Blood-brain and gut barriers are made more brittle and hyperpermeable by stress-induced, exaggerated inflammation. This may be brought on by dysbiosis, an imbalance in microbial populations and changes to the gut-brain axis, which is crucial for the synthesis of the mood-regulating neurotransmitter serotonin. |