Central changes associated with chronic pelvic pain and endometriosis

Jennifer Brawn, Brawn J, Matteo Morotti, Krina T. Zondervan, Christian M. Becker, Becker CM, Katy Vincent
Human Reproduction Update · 2014 · vol. 20(5) , pp. 737–747 · doi:10.1093/humupd/dmu025 · PMID:24920437 · PMC4501205 · W2136897269
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Chronic pelvic pain in women is linked to central nervous system changes including altered responses to pain, structural brain modifications, hypothalamic-pituitary-adrenal axis and autonomic nervous system dysfunction, and psychological distress.

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This paper is a narrative review of evidence for central (CNS) changes associated with chronic pelvic pain (CPP), including functional measures during experimentally delivered painful stimuli (psychophysical responses, hypothalamic–pituitary–adrenal axis, and autonomic nervous system activity) and structural findings from neuroimaging (fMRI/PET). It synthesizes studies up to 2013 and reports that women with CPP often show increased behavioral responses to somatic or visceral noxious stimuli, but results are inconsistent across stimulation sites and pain measures, with the authors attributing this to methodological differences and noting that behavioral changes cannot distinguish peripheral from central mechanisms. The review further discusses how neuroimaging studies in other pelvic pain conditions (and concepts such as central sensitization and the “brain-gut axis”) support CNS involvement, while stating it is not a systematic review and that functional imaging has not yet been broadly applied to endometriosis-associated pain at the time covered. Relevance to endometriosis: the paper highlights that endometriosis is “such a common finding” among women with CPP presenting to gynecologists and calls out evidence of enhanced responses to distant noxious stimulation in endometriosis studies, even though it emphasizes that there were no (or very limited) endometriosis-focused neuroimaging data by the search end date.

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Abstract

BACKGROUND: Chronic pelvic pain (CPP) is a significant public health problem with 1 million affected women in the UK. Although many pathologies are associated with CPP, the pain experienced is often disproportionate to the extent of disease identified and frequently no pathology is found (chronic pelvic pain syndrome). The central nervous system (CNS) is central to the experience of pain and chronic pain conditions in general are associated with alterations in both the structure and function of the CNS. This review describes the available evidence for central changes in association with conditions presenting with CPP. METHODS: A detailed literature search was performed to identify relevant papers, however, this is not a systematic review. RESULTS: CPP is associated with central changes similar to those identified in other pain conditions. Specifically these include, alterations in the behavioural and central response to noxious stimulation, changes in brain structure (both increases and decreases in the volume of specific brain regions), altered activity of both the hypothalamic-pituitary-adrenal axis and the autonomic nervous system (ANS) and psychological distress. CONCLUSIONS: The evidence reviewed in this paper demonstrates that CPP is associated with significant central changes when compared with healthy pain-free women. Moreover, the presence of these changes has the potential to both exacerbate symptoms and to predispose these women to the development of additional chronic conditions. These findings support the use of adjunctive medication targeting the CNS in these women.
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Is

Endometriosis is an unusual condition because of the potential of a variety of different mechanisms to generate pain (see Fig. 3 ). These include direct compression/infiltration of nerves by the lesions, inflammatory pain due to the enhanced inflammatory environment of the pelvis and ‘neuropathic’ pain secondary to damage of pelvic nerves during surgery or of the new nerves directly infiltrating the lesions ( Stratton and Berkley, 2011 ). The disruption of the HPA axis may be particularly important in endometriosis because of its potential to enhance both the pelvic inflammatory environment and allow increased growth of lesions. A similar situation has been previously proposed to occur in rheumatoid arthritis ( Straub and Cutolo, 2001 ). Moreover, many women with endometriosis are likely to have significant concerns about their fertility. These concerns could be expected to increase both anxiety and pain catastrophising (an exaggerated negative response in anticipation of pain ( Quartana et al. , 2009 )) thereby amplifying the pain experience. Furthermore, women with fertility concerns are more likely to undergo surgical treatment of their disease ( Dunselman et al. , 2014 ), thereby increasing the potential for further damage to pelvic and endometriotic nerves. Similarly, the association of endometriosis with dyspareunia could be expected to increase psychological distress in these women ( Meana et al. , 1999 ). Furthermore, if this symptom significantly impacts on their relationship, both self-esteem and social support may be reduced, potentially further worsening their pain experience ( Culley et al. , 2013 ). It is plausible that these central changes contribute to the well-established disparity between the extent of disease observed at laparoscopy and the pain experienced ( Vercellini et al. , 2007 ) and to the persistence of pain despite adequate surgical treatment. However, further work specifically assessing central changes in women with proven endometriosis and their influence on pain symptoms and the response to treatment are needed.

Brain

Perhaps surprisingly, many chronic pain conditions have been associated with a reduction in brain volume. Of particular note, these changes are not global across the brain but occur in specific regions which are functionally involved in the processing of pain ( May, 2011 ). The mechanisms behind these alterations in brain volume are not completely understood but may include a direct neurotoxic effect of repeated episodes of pain leading to neuronal atrophy or death, an effect of altered metabolic activity or neurotransmitter concentration, neurotoxic effects of drugs, neurodegeneration secondary to pain-related inactivity, and an effect related to psychological correlates such as anxiety and depression ( May, 2008 , 2011 ). Morphological studies exist for a variety of non-pelvic chronic pain conditions including chronic low back pain, fibromyalgia and headache. The volume of the grey matter in the anterior cingulate cortex is reduced in almost all these conditions; however, reductions are also commonly seen in the volume of other regions particularly the thalamus, insula and prefrontal cortices ( May, 2011 ). In many cases the volume of specific brain regions correlated with the duration of the symptom suggesting that these volumetric changes are a consequence rather than a cause of the pain. Volumetric studies have also been undertaken in women with dysmenorrhoea, provoked vestibulodynia and CPP, both without an obvious cause, and related to endometriosis and IBS ( Supplementary data, Table SIV ). Interestingly, although decreases in grey matter were observed in many pain processing regions, areas with an increased volume were also observed ( Schweinhardt et al. , 2008 ; Blankstein et al. , 2010 ; Seminowicz et al. , 2010 ; Tu et al. , 2010 , 2013 ; As-Sanie et al. , 2012 ). Although these increases were observed in different brain regions from those where reductions in volume have been observed in other conditions, these regions are also known to be involved in the processing of noxious stimuli. A number of reasons have been proposed to explain why increases in brain volume are seen with these specific pain conditions in contrast to the other conditions investigated, including the fact that the patients are generally younger, pain is intermittent/cyclical/provoked as opposed to continuous and that most women with these conditions do not use large doses of pain modifying drugs for a prolonged time period ( Schweinhardt et al. , 2008 ). Of particular interest is the recent elegantly designed study by As-Sanie and colleagues ( As-Sanie et al. , 2012 ). They investigated 23 women with CPP with and without laparoscopically proven endometriosis, in addition to women in whom endometriosis had been found but who did not suffer with CPP and compared each group to healthy pain-free controls. As expected the women with CPP (whether or not there was endometriosis present) had reduced brain volume in the thalamus, and moreover there were also reductions in the cingulate, insula and putamen in those with endometriosis-related CPP. However, the more interesting finding was that women with endometriosis but without CPP had an increase in the volume of their periaqueductal grey (PAG) ( Fig. 2 ). Furthermore, the volume of the PAG in these women correlated positively with the amount of pressure required to induce pain (i.e. the bigger their PAG the more pressure they could tolerate before reporting pain). The authors suggest that this may be due to the PAG’s role in descending pain inhibition and potentially may explain why some women with endometriosis have little or no pain despite a significant burden of disease. Functional imaging studies in this domain will hopefully help elucidate the PAG’s role in the pain associated with endometriosis, specifically whether women with endometriosis but without CPP might be better able to engage descending pain inhibition circuitry.

Intro

Chronic pelvic pain (CPP) is a major public health problem throughout the developed world ( Mathias et al. , 1996 ; Zondervan et al. , 2001 ; Grace and Zondervan, 2004 ; Garcia-Perez et al. , 2010 ). In the UK alone it affects >1 million women and has been recently highlighted as a key area of unmet need ( Donaldson, 2009 ). CPP can present at all ages, with studies suggesting that the prevalence increases with age (18.2/1000 in 15–20 year olds; 27.6/1000 in women over 60) ( Zondervan et al. , 1999a , b ). Yet despite being as common as asthma and back pain ( Zondervan et al. , 1999a , b ), with a significant financial cost to both the individual and society ( Mathias et al. , 1996 ), there is frequently a significant delay in diagnosis and treatment. In fact, studies suggest that up to 50% of women have not received a diagnosis after many years follow-up ( Grace, 1995 ; Zondervan et al. , 1999a , b ; Grace and Zondervan, 2004 ). A variety of pelvic pathologies are associated with CPP in women, including endometriosis, adenomyosis or chronic infection and it can be associated with functional disorders of the bowel (irritable bowel syndrome (IBS)) and the bladder (interstitial cystitis/painful bladder syndrome (IC/PBS)). In many cases, however, detailed investigation of the pelvis/pelvic viscera via both imaging and surgery reveals no abnormality (chronic pelvic pain syndrome (CPPS)) ( Baranowski et al. , 2012 ). Furthermore, even when pathology is identified and treated the pain may still persist, suggesting that the pathology was either an incidental finding or that other mechanisms continue to generate pain without the need for a peripheral input ( Baranowski, 2009 ). CPP has recently been defined as ‘chronic or persistent pain perceived in structures related to the pelvis of either men or women. It is often associated with negative cognitive, behavioural, sexual and emotional consequences as well as with symptoms suggestive of lower urinary tract, sexual, bowel, pelvic floor or gynaecological dysfunction’ ( Baranowski et al. , 2012 ). Despite this definition acknowledging that the patient and clinician localize the pain as being perceived in the specified anatomical area, the conscious experience of pain is the result of co-ordinated activity within the central nervous system (CNS) ( Tracey and Mantyh, 2007 ). If the focus is shifted away from the pelvis and onto the CNS, it can be seen that women with CPP do exhibit central changes analogous to those observed in other chronic pain conditions ( Apkarian et al. , 2005 ; Tracey and Bushnell, 2009 ; Kaya et al. , 2013 ). This review will describe the available evidence for central changes in association with conditions presenting with CPP, focussing on both functional (specifically the response during experimentally-delivered painful stimulation, the activity of the hypothalamic–pituitary–adrenal (HPA) axis and the ANS) and structural alterations. As endometriosis is such a common finding in women with CPP presenting to gynaecologists, we will highlight areas where there is evidence relating specifically to endometriosis. We will then discuss the implications of these changes in CPP, before considering whether endometriosis is a ‘special case’ that is particularly vulnerable to central changes.

Changes

Activation of the HPA axis is central to the stress response ( Frodl and O’Keane, 2013 ). Given that chronicpain can be considered as a repeated stressor, both physiologically and psychologically, it is probably not surprising that dysfunction in the activity of the HPA axis is an almost universal finding in chronic pain conditions ( Griep et al. , 1998 ; Gaab et al. , 2005 ; Galli et al. , 2009 ). Moreover, cortisol, as one of the principal players in the HPA axis, appears to be central to the phenomenon of stress-induced analgesia ( Filaretov et al. , 1996 ) and therefore a reduction in cortisol levels secondary to dysfunction of the HPA axis may exacerbate pain. The findings in CPP are consistent with other chronic pain conditions ( Griep et al. , 1998 ; Gaab et al. , 2005 ; Galli et al. , 2009 ). Thus, abnormally low cortisol levels have been observed in women with endometriosis and CPP ( Petrelluzzi et al. , 2008 ), dysmenorrhoea ( Vincent et al. , 2011 ) and provoked vulvodynia ( Ehrstrom et al. , 2009 ) and replicated over repeated measurements ( Petrelluzzi et al. , 2008 ; Vincent et al. , 2011 ). In two of these studies, levels of reported stress were also assessed and found to be higher in patients than controls, despite their lower cortisol levels ( Petrelluzzi et al. , 2008 ; Ehrstrom et al. , 2009 ). The mechanism(s) by which suppression of the HPA axis is produced are as yet unclear. Burnout of the system has been proposed as one possibility ( Hellhammer and Wade, 1993 ; Fries et al. , 2005 ) and the recent finding that cortisol levels were negatively correlated with the duration of dysmenorrhoea ( Vincent et al. , 2011 ) would be consistent with this, suggesting that HPA axis suppression is a consequence not a cause of their symptoms. In women with endometriosis, the circadian pattern of cortisol secretion was maintained but suppression of cortisol secretion occurred throughout the day ( Petrelluzzi et al. , 2008 ). In view of the negative impact of chronic stress on important physiological processes including the immune system and memory function ( McEwen, 2005 ), it has been proposed that suppression of HPA axis activity might in fact be a protective mechanism ( Fries et al. , 2005 ). However, as we will discuss below, a reduction in serum cortisol levels would be expected to exacerbate symptoms from any underlying infective or inflammatory pathology.

Methods

Literature searches were conducted using CPP OR CPPS OR known individual causes of CPP (including IBS, endometriosis, IC) AND (i) brain/CNS/nervous system/central or (ii) MRI/fMRI/PET/imaging. Reference lists from other publications were also examined for any missed studies from the initial literature search. We included studies published up until 2013. However, it should be stated that this is not a systematic review.

Autonomic

It has been suggested that abnormal functioning of the ANS might responsible for some of the symptoms associated with IBS ( Bockus et al. , 1928 ). In healthy controls, experimentally increasing sympathetic activity has been shown to heighten visceral organ sensitivity to distension ( Iovino et al. , 1995 ). In women with IBS, altered ANS functioning (increased sympathetic and/or decreased parasympathetic activity) has been observed during sleep ( Thompson et al. , 2002 ), over a 24 h period ( Heitkemper et al. , 1998 ), and after stimulation of the sympathetic nervous system ( Waring et al. , 2004 ) when compared with healthy women. In response to painful distension of the sigmoid colon and rectum, individuals with IBS have demonstrated decreases in parasympathetic and increases in sympathetic nervous system activity when compared with healthy controls (although this finding was only significant in men with IBS) ( Tillisch et al. , 2005 ). Whether these changes in ANS activity are unique to IBS or, as with the other changes described here, are common to all patients with CPP is as yet unclear. A recent questionnaire study, assessed for the presence of autonomic symptoms (such as vasomotor symptoms, orthostatic intolerance and sleep disorder) in a small cohort of women with CPP ( n = 16) and pain-free controls ( n = 15) ( Janicki et al. , 2013 ). They found a significantly higher incidence of autonomic symptoms in the women with CPP, however, there are a number of difficulties in interpreting these results. Firstly, the autonomic symptom profile included symptoms relating to bowel and bladder function yet ten of the fifteen CPP patients had pain with a full bladder and/or with bowel movement. Secondly, there was no assessment of drug use in the CPP cohort and, as the authors describe, many of the autonomic symptoms may be secondary to the drugs prescribed to treat their pain. Furthermore, the sample size was small and the symptoms not validated by a medical practitioner. However, this is certainly an area that deserves further investigation in the future.

Conclusions

The evidence reviewed in this paper demonstrates that CPP, whilst perceived as a peripheral (pelvic) condition, is in fact associated with significant central changes when compared with healthy pain-free women. These findings support the use of adjunctive medication targeting the CNS (such as amitriptyline, gabapentin, duloxetine, etc.) in women with CPP. This is common practice in other chronic pain conditions ( Dworkin et al. , 2010 ; Richards et al. , 2012 ) but is currently poorly investigated in CPP specifically ( Sator-Katzenschlager et al. , 2005 ; Horne et al. , 2012 ). Although it remains to be ascertained whether central changes are a cause, effect or both of the painful symptoms, it appears likely that their presence has the potential to not only exacerbate symptoms, but also to predispose these women to the development of additional chronic conditions. The extent to which these central changes are reversible with treatment remains unknown. However, these findings support the idea that pain should be treated promptly even in the absence of identifiable pathology. Such prompt treatment, as well as being welcomed by the patient, may prevent development or progression of central changes and potentially development of other symptoms/pain conditions, in addition to improving symptoms from any other pain conditions already present ( Giamberardino et al. , 2010 ). It is of particular concern that many of the symptoms of CPP start in adolescence or early adult life ( Zondervan et al. , 1999a , b ; Brosens et al. , 2013 ), a time when the CNS is very plastic ( Blakemore and Choudhury, 2006 ; Kalia, 2008 ) and thus potentially more vulnerable to repeated episodes of pain. Whilst future longitudinal studies are required to assess the impact of pelvic pain on brain development in adolescents and young women, strategies for reducing the amount of pain experienced are likely to be of particular importance in these patients.

Implications

A major criticism of many of the studies cited in this review is that they are ‘snapshot’ studies and therefore they can only inform us about central factors that occur in association with chronic pain, rather than giving us any information about cause and effect. Unfortunately, we currently know very little about why some people develop chronic pain. It is extremely difficult to undertake longitudinal studies, evaluating the factors that predispose to the development of chronic pain and assessing the central changes that occur after such pain has developed. Whilst these are clearly questions that future large collaborative studies need to answer, there are many implications of the central features of chronic pain that have been described above which justify their identification and treatment where possible, no matter what their aetiology might be. Many of the pathologies associated with CPP in women have an infective or inflammatory component (endometriosis, adenomyosis, potentially interstitial cystitis/painful bladder syndrome (IC/PBS), chronic pelvic inflammatory disease (PID), etc.), therefore a reduction in circulating glucocorticoids would be expected to exacerbate these pathologies ( Silverman and Sternberg, 2012 ). Such an increase in disease burden alone could be expected to intensify symptoms. Additionally, many of the changes described above can aggravate pain even if the peripheral nociceptive input stays constant. These include a loss of a variety of endogenous analgesic mechanisms including that mediated by cortisol and an amplification of pain by psychological factors such as anxiety and depression ( Tracey and Mantyh, 2007 ). Furthermore, the development of central sensitization, as has been demonstrated in a number of conditions associated with CPP ( Kaya et al. , 2013 ), can lead to the generation of pain without a peripheral noxious input potentially at least partly explaining the pain that persists despite optimum treatment of identified pathology. It is well known that chronic pain conditions cluster and that having one pain condition can increase the likelihood of developing another. This is true for conditions within the pelvis (e.g. IBS and IC/PBS ( Rodriguez et al. , 2009 )) and at distant sites (e.g. CPP and migraine ( Karp et al. , 2011 ; Yang et al. , 2012 )). There are a number of reasons as to why this might occur including common predisposing factors, such as genetics ( Diatchenko et al. , 2007 ) or psychological/cognitive state (for review, see Blackburn-Munro (2004) ), and similar neural mechanisms ( Giamberardino et al. , 2010 ). However, it is also plausible that the central changes secondary to one chronic pain condition could then predispose to the development of another ( Woolf, 2011 ). For example, a reduction in circulating cortisol could increase the chances of repeated urinary tract infections, or central sensitization could predispose to the development of chronic whiplash after a minor car accident. In this context, the central changes observed in women with dysmenorrhoea ( Tu et al. , 2009 , 2010 , 2013 ; Vincent et al. , 2011 ) are of particular concern given the high prevalence of dysmenorrhoea in adolescents and young women. The correlation between CPP and other clinical conditions is not exclusive to those in the realm of pain. Chronic fatigue syndrome (CFS) has been correlated with vulvodynia ( Arnold et al. , 2007 ) and IBS ( Whitehead et al. , 2002 ), whilst endometriosis is associated with a variety of autoimmune and endocrine conditions including hypothyroidism, systemic lupus erythematosus and multiple sclerosis ( Sinaii et al. , 2002 ). Other chronic conditions have also been associated with HPA axis dysfunction, including CFS and major depression, as has post-traumatic stress disorder ( Yehuda et al. , 1991 ; Pariante and Lightman, 2008 ; Papadopoulos and Cleare, 2012 ). Thus, activity of the HPA axis may conceivably be a biological mechanism relating these conditions. Moreover, it could underlie the frequently discussed, though not well proven ( Raphael et al. , 2004 ), link between abuse and chronic pain.

Psychological

Many chronic pain conditions are comorbid with depression and anxiety (for review, see Blackburn-Munro and Blackburn-Munro (2001) ). Negative psychological states potentially put individuals at increased risk for developing or exacerbating chronic pain. However, it is important to remember that psychological dysfunction can also be a consequence of the pain (for reviews, see Blackburn-Munro and Blackburn-Munro (2001) and Blackburn-Munro (2004) ). Psychological distress has been observed in women with CPP. Thus even women who only suffer with dysmenorrhoea (as opposed to pain throughout the month) have increased tendencies for depression and anxiety ( Dorn et al. , 2009 ), although this is not a universal finding ( Vincent et al. , 2011 ). Similarly, women with endometriosis ( Sepulcri Rde and do Amaral, 2009 ; Smorgick et al. , 2013 ) and provoked vestibulodynia ( Nunns and Mandal, 1997 ) are more likely to have anxiety or depression, but may otherwise be psychologically healthy ( Eriksen et al. , 2008 ). Neuroimaging studies have shown that psychological factors can augment the pain experience by specific mechanisms that are different from those observed when the noxious input is increased (for review, see Tracey and Mantyh (2007) ). Thus anxiety amplifies pain by increasing activity within the hippocampus and entorhinal cortex ( Ploghaus et al. , 2001 ), whilst depression enhances the affective component of pain, increasing unpleasantness, and appears to disrupt activity within a network of brain regions including the amygdala and inferior frontal gyrus ( Berna et al. , 2010 ). In the context of dysmenorrhoea, Tu and colleagues observed regionally specific (prefrontal and orbitofrontal cortices) metabolic increases in the brain during dysmenorrhoea, which they suggest may be related to negative psychological symptoms ( Tu et al. , 2009 ).

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Condition tags

endometriosischronic_pelvic_pain

MeSH descriptors

Chronic Pain Endometriosis Pelvic Pain Brain Brain Brain Chronic Pain Chronic Pain Chronic Pain Chronic Pain Endometriosis Endometriosis Female Humans Hypothalamo-Hypophyseal System Hypothalamo-Hypophyseal System Pelvic Pain Pelvic Pain Pelvic Pain Pelvic Pain

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