Katy Vincent

Dysmenorrhoea is associated with central changes in otherwise healthy women.

&NA; Patients with chronic pain conditions demonstrate altered central processing of experimental noxious stimuli, dysfunction of the hypothalamic–pituitary–adrenal axis, and reduced quality of life. Dysmenorrhoea is not considered a chronic pain condition, but is associated with enhanced behavioural responses to experimental noxious stimuli. We used behavioural measures, functional magnetic resonance imaging, and serum steroid hormone levels to investigate the response to experimental thermal stimuli in otherwise healthy women, with and without dysmenorrhoea. Women with dysmenorrhoea reported increased pain to noxious stimulation of the arm and abdomen throughout the menstrual cycle; no menstrual cycle effect was observed in either group. During menstruation, deactivation of brain regions in response to noxious stimulation was observed in control women but not in women with dysmenorrhoea. Without background pain (ie, in nonmenstrual phases), activity in the entorhinal cortex appeared to mediate the increased responses in women with dysmenorrhoea. Mean cortisol was significantly lower in women with dysmenorrhoea and was negatively correlated with the duration of the symptom. Additionally, women with dysmenorrhoea reported significantly lower physical but not mental quality of life. Thus, many features of chronic pain conditions are also seen in women with dysmenorrhoea: specifically a reduction in quality of life, suppression of the hypothalamic–pituitary–adrenal axis, and alterations in the central processing of experimental noxious stimuli. These alterations persist when there is no background pain and occur in response to stimuli at a site distant from that of the clinical pain. These findings indicate the potential importance of early and adequate treatment of dysmenorrhoea. In common with chronic pain patients, women with dysmenorrhoea demonstrate altered central processing of noxious stimuli and reduced serum cortisol and quality of life.

Central changes associated with chronic pelvic pain and endometriosis

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.

Pain scoring in endometriosis: entry criteria and outcome measures for clinical trials. Report from the Art and Science of Endometriosis meeting

Standardized entry criteria and outcome measures for clinical trials in endometriosis-related pain would facilitate the comparison of trial results and the production of systematic reviews, improving evidence-based practice in this area. This report summarizes the recommendations from an international meeting for these criteria.

World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project: III. Fluid biospecimen collection, processing, and storage in endometriosis research

Objective To harmonize standard operating procedures (SOPs) and standardize the recording of associated data for collection, processing, and storage of human tissues relevant to endometriosis. Design An international collaboration involving 34 clinical/academic centers and three industry collaborators from 16 countries on five continents. Setting In 2013, two workshops were conducted followed by global consultation, bringing together 54 leaders in endometriosis research and sample processing from around the world. Patient(s) None. Intervention(s) Consensus SOPs were based on: 1) systematic comparison of SOPs from 24 global centers collecting tissue samples from women with and without endometriosis on a medium or large scale (publication on >100 cases); 2) literature evidence where available, or consultation with laboratory experts otherwise; and 3) several global consultation rounds. Main Outcome Measure(s) Standard recommended and minimum required SOPs for tissue collection, processing, and storage in endometriosis research. Result(s) We developed “recommended standard” and “minimum required” SOPs for the collection, processing, and storage of ectopic and eutopic endometrium, peritoneum, and myometrium, and a biospecimen data collection form necessary for interpretation of sample-derived results. Conclusion(s) The EPHect SOPs allow endometriosis research centers to decrease variability in tissue-based results, facilitating between-center comparisons and collaborations. The procedures are also relevant to research into other gynecologic conditions involving endometrium, myometrium, and peritoneum. The consensus SOPs are based on the best available evidence; areas with limited evidence are identified as requiring further pilot studies. The SOPs will be reviewed based on investigator feedback and through systematic triannual follow-up. Updated versions will be made available at: http://endometriosisfoundation.org/ephect.

Peripheral changes in endometriosis-associated pain

BACKGROUND Pain remains the cardinal symptom of endometriosis. However, to date, the underlying mechanisms are still only poorly understood. Increasing evidence points towards a close interaction between peripheral nerves, the peritoneal environment and the central nervous system in pain generation and processing. Recently, studies demonstrating nerve fibres and neurotrophic and angiogenic factors in endometriotic lesions and their vicinity have led to increased interest in peripheral changes in endometriosis-associated pain. This review focuses on the origin and function of these nerves and factors as well as possible peripheral mechanisms that may contribute to the generation and modulation of pain in women with endometriosis. METHODS We conducted a systematic search using several databases (PubMed, MEDLINE, EMBASE and CINAHL) of publications from January 1977 to October 2013 to evaluate the possible roles of the peripheral nervous system in endometriosis pathophysiology and how it can contribute to endometriosis-associated pain. RESULTS Endometriotic lesions and peritoneal fluid from women with endometriosis had pronounced neuroangiogenic properties with increased expression of new nerve fibres, a shift in the distribution of sensory and autonomic fibres in some locations, and up-regulation of several neurotrophins. In women suffering from deep infiltrating endometriosis and bowel endometriosis, in which the anatomical distribution of lesions is generally more closely related to pelvic pain symptoms, endometriotic lesions and surrounding tissues present higher nerve fibre densities compared with peritoneal lesions and endometriomas. More data are needed to fully confirm a direct correlation between fibre density in these locations and the amount of perceived pain. A better correlation between the presence of nerve fibres and pain symptoms seems to exist for eutopic endometrium. However, this appears not to be exclusive to endometriosis. No correlation between elevated neurotrophin levels and pain severity appears to exist, suggesting the involvement of other mediators in the modulation of pain. CONCLUSIONS The increased expression of neurotrophic factors and nerve fibres in endometriotic lesions, eutopic endometrium and the peritoneum imply a role of such peripheral changes in the pathogenesis of endometriosis-associated pain. However, a clear link between these findings and pain in patients with endometriosis has so far not been demonstrated.

World Endometriosis Research Foundation Endometriosis Phenome and biobanking harmonization project: II. Clinical and covariate phenotype data collection in endometriosis research

Objective To harmonize the collection of nonsurgical clinical and epidemiologic data relevant to endometriosis research, allowing large-scale collaboration. Design An international collaboration involving 34 clinical/academic centers and three industry collaborators from 16 countries on five continents. Setting In 2013, two workshops followed by global consultation, bringing together 54 leaders in endometriosis research. Patients None. Intervention(s) Development of a self-administered endometriosis patient questionnaire (EPQ), based on [1] systematic comparison of questionnaires from eight centers that collect data from endometriosis cases (and controls/comparison women) on a medium to large scale (publication on >100 cases); [2] literature evidence; and [3] several global consultation rounds. Main Outcome Measure(s) Standard recommended and minimum required questionnaires to capture detailed clinical and covariate data. Result(s) The standard recommended (EPHect EPQ-S) and minimum required (EPHect EPQ-M) questionnaires contain questions on pelvic pain, subfertility and menstrual/reproductive history, hormone/medication use, medical history, and personal information. Conclusion(s) The EPQ captures the basic set of patient characteristics and exposures considered by the WERF EPHect Working Group to be most critical for the advancement of endometriosis research, but is also relevant to other female conditions with similar risk factors and/or symptomatology. The instruments will be reviewed based on feedback from investigators, and–after a first review after 1 year–triannually through systematic follow-up surveys. Updated versions will be made available through http://endometriosisfoundation.org/ephect.

Brain imaging reveals that engagement of descending inhibitory pain pathways in healthy women in a low endogenous estradiol state varies with testosterone

Summary Activity in key regions of the descending pain inhibitory system varies with testosterone in women in both a natural and induced low endogenous estradiol state. Abstract The combined oral contraceptive pill (COCP) has been implicated in the development of a number of chronic pain conditions. Modern COCP formulations produce a low endogenous estradiol, low progesterone environment similar to the early follicular phase of the natural menstrual cycle, with a variable effect on serum androgen levels. We used behavioural measures and functional magnetic resonance imaging to investigate the response to experimental thermal stimuli in healthy women, in both a natural and COCP‐induced low endogenous estradiol state, to investigate whether alterations in central pain processing may underlie these observations in COCP users. Although COCP users overall did not require lower temperatures to obtain a fixed pain intensity, alterations in the brain response to these stimuli were observed. In a subgroup of COCP users with significantly reduced serum testosterone, however, lower temperatures were required. Region‐of‐interest analysis revealed that within key regions of the descending pain inhibitory system, activity in response to noxious stimulation varied with serum testosterone levels in both groups of women. Of particular interest, in COCP users, activity in the rostral ventromedial medulla increased with increasing testosterone and in those women with low testosterone, was significantly reduced compared to controls. These findings suggest that, in a low endogenous estradiol state, testosterone may be a key factor in modulating pain sensitivity via descending pathways. Specifically, failure to engage descending inhibition at the level of the rostral ventromedial medulla may be responsible for the reduction in temperature required by COCP users with low circulating testosterone.

Gabapentin for the Management of Chronic Pelvic Pain in Women (GaPP1) : A Pilot Randomised Controlled Trial

Chronic pelvic pain (CPP) affects 2.1–24% of women. Frequently, no underlying pathology is identified, and the pain is difficult to manage. Gabapentin is prescribed for CPP despite no robust evidence of efficacy. We performed a pilot trial in two UK centres to inform the planning of a future multicentre RCT to evaluate gabapentin in CPP management. Our primary objective was to determine levels of participant recruitment and retention. Secondary objectives included estimating potential effectiveness, acceptability to participants of trial methodology, and cost-effectiveness of gabapentin. Women with CPP and no obvious pelvic pathology were assigned to an increasing regimen of gabapentin (300-2700mg daily) or placebo. We calculated the proportion of eligible women randomised, and of randomised participants who were followed up to six months. The analyses by treatment group were by intention-to-treat. Interviews were conducted to evaluate women’s experiences of the trial. A probabilistic decision analytical model was used to estimate cost-effectiveness. Between September 2012–2013, 47 women (34% of those eligible) were randomised (22 to gabapentin, 25 to placebo), and 25 (53%) completed six-month follow-up. Participants on gabapentin had less pain (BPI difference 1.72 points, 95% CI:0.07–3.36), and an improvement in mood (HADS difference 4.35 points, 95% CI:1.97–6.73) at six months than those allocated placebo. The majority of participants described their trial experience favorably. At the UK threshold for willingness-to-pay, the probabilities of gabapentin or no treatment being cost-effective are similar. A pilot trial assessing gabapentin for CPP was feasible, but uncertainty remains, highlighting the need for a large definitive trial. Trial registration Controlled-Trials.com ISRCTN45178534

Chronic pelvic pain in women

Chronic pelvic pain is a major public health problem for women throughout the developed world. The complex innervation of the pelvis and the anatomical proximity of pelvic viscera mean this symptom frequently overlaps traditional medical specialties, leading to diagnostic delay and frequently inadequate treatment. Careful history taking and examination can in itself be therapeutic and will likely identify a number of causal and perpetuating factors which should be managed within the context of a multidisciplinary clinic.

Presence of mental imagery associated with chronic pelvic pain: a pilot study.

Objective To ascertain whether a small sample of patients with chronic pelvic pain experienced any pain-related cognitions in the form of mental images. Patients Ten women with chronic pelvic pain consecutively referred from a tertiary referral center by the physicians in charge of their treatment. Outcome measures An interview was used to determine the presence, emotional valence, content, and impact of cognitions about pain in the form of mental images and verbal thoughts. The Brief Pain Inventory (BPI), Pain Catastrophizing Scale (PCS), Spontaneous Use of Imagery Scale (SUIS), and Hospital Anxiety and Depression Scale (HADS) were completed. Results In a population of patients with a prolonged duration of pain and high distress, all patients reported experiencing cognitions about pain in the form of mental images. For each patient, the most significant image was both negative in valence and intrusive. The associated emotional-behavioral pattern could be described within a cognitive behavioral therapy framework. Eight patients also reported coping imagery. Conclusion Negative pain-related cognitions in the form of intrusive mental imagery were reported by women with chronic pelvic pain. Targeting such imagery has led to interesting treatment innovation in the emotional disorders. Thus, imagery, hitherto neglected in pain phenomenology, could provide a novel target for cognitive behavioral therapy in chronic pain. These exciting yet preliminary results require replication and extension in a broader population of patients with chronic pain.