OBJECTIVE: To determine whether women with chronic pelvic pain and variable degrees of endometriosis demonstrate altered pain sensitivity relative to pain-free healthy women in a control group and whether such differences are related to the presence or severity of endometriosis or comorbid pain syndromes.
METHODS: Four patient subgroups (endometriosis with chronic pelvic pain [n=42], endometriosis with dysmenorrhea [n=15], pain-free endometriosis [n=35], and chronic pelvic pain without endometriosis [n=22]) were each compared with 30 healthy women in a control group in this cross-sectional study. All patients completed validated questionnaires regarding pain symptoms and underwent screening for comorbid pain disorders. Pain sensitivity was assessed by applying discrete pressure stimuli to the thumbnail using a previously validated protocol.
RESULTS: While adjusting for age and education, pain thresholds were lower in all subgroups of women with pelvic pain relative to healthy women in the control group (all P values <.01). There was no difference in pain thresholds when comparing patients with endometriosis without pelvic pain with healthy women in the control group (mean difference 0.02 kg/m2, 95% confidence interval −0.43 to 0.47). The presence and severity of endometriosis and number of comorbid pain syndromes were not associated with a difference in pain thresholds.
CONCLUSION: Women with chronic pelvic pain demonstrate increased pain sensitivity at a nonpelvic site compared with healthy women in a control group, which is independent of the presence or severity of endometriosis or comorbid pain syndromes. These findings support the notion that central pain amplification may play a role in the development of pelvic pain and may explain why some women with pelvic pain do not respond to therapies aimed at eliminating endometriosis lesions.
LEVEL OF EVIDENCE: II
Pelvic pain is associated with increased pain sensitivity, which is unrelated to the presence or severity of endometriosis or comorbid pain syndromes.
Departments of Obstetrics and Gynecology, Anesthesiology, and Internal Medicine (Rheumatology), University of Michigan Health Center, Ann Arbor, Michigan; and the Department of Obstetrics and Gynecology, Northshore University Health System, Chicago, Illinois.
Corresponding author: Sawsan As-Sanie, MD, MPH, Department of Obstetrics and Gynecology, University of Michigan Health System, L4100 Women's Hospital, 1500 East Medical Center Drive, Ann Arbor, MI 48109; e-mail: email@example.com.
Supported in part by National Institutes of Health (NIH) K12HD001438, NIH UL1RR024986, and the Bayer Droegemueller Award in Clinical Research.
Presented in part at the Society for Gynecologic Investigation annual scientific meeting, March 17–21, 2009, Glasgow, United Kingdom.
Financial Disclosure Dr. Tu receives research funding from AbbVie. The other authors did not report any potential conflicts of interest.
Chronic pelvic pain affects 15–20% of reproductive-aged women, creating direct health care costs of $2.8 billion annually.1–3 Despite its high prevalence and negative effect, little is known about the pathophysiology underlying the development and persistence of chronic pelvic pain. Like with many other chronic pain syndromes, the presence and severity of pelvic pathology such as endometriosis do not correlate with symptom burden.4–7 Standard medical and surgical therapies targeting endometriosis lesions are not consistently effective and pain frequently recurs even without visible disease at repeat laparoscopy.8–10 Against this background, endometriosis must be viewed as an important but insufficient risk factor for the development of pelvic pain. Thus, characterization of the underlying mechanisms that lead to chronic pain is necessary to develop targeted treatment strategies for women who are not responsive to traditional therapies for endometriosis and other causes of pelvic pain.
Using various quantitative sensory testing and neuroimaging techniques, central amplification of pain processing has been shown to be an underlying mechanism of persistent pain in many chronic pain syndromes.11–13 Similarly, there is early evidence that central pain amplification may also play an important role in the pathophysiology of chronic pelvic pain. For example, prior studies show heightened pain sensitivity to experimental thermal and mechanical stimuli in women with endometriosis-associated pelvic pain relative to pain-free women in a control group.14–16 However, these smaller studies were not designed to determine whether the presence or severity of endometriosis or comorbid pain syndromes is associated with differences in pain processing. This is important because comorbid pain syndromes, which are highly prevalent in women with pelvic pain, are known to be independently associated with alterations in nociceptive processing and could provide an alternate explanation for observed differences in pain sensitivity in these women. Thus, the aim of this study was to determine whether women with pelvic pain and variable degrees of endometriosis demonstrate alterations in pain sensitivity and whether such differences are related to the presence or severity of endometriosis or comorbid pain syndromes.
MATERIALS AND METHODS
Between June 2006 and April 2010, women with endometriosis or chronic pelvic pain and healthy women without pelvic pain or known endometriosis were recruited to participate in this observational study. All participants were premenopausal women aged 18–52 years who had not undergone prior hysterectomy or bilateral oophorectomy. Women with endometriosis or chronic pelvic pain were recruited from a tertiary care endometriosis and pelvic pain referral center as well as through advertisement to the local community. Pain-free healthy women for the control group were recruited through local advertisements. All participants received $40 for participating in the study. Approval for this study was obtained from the University of Michigan institutional review board and all participants provided informed, signed consent. A subgroup of these participants also participated in a previously published study of regional cerebral gray matter differences in women with chronic pelvic pain.17
Potential participants were screened by phone interview. Those with endometriosis or chronic pelvic pain were invited to participate if they underwent pelvic surgery within 5 years and reported a history of either surgically confirmed endometriosis or chronic pelvic pain. Women in the control group were pain-free without symptoms of dysmenorrhea or pelvic pain, and these women had no known history of endometriosis or any other chronic pain syndrome. All potential participants were screened with the Mini-International Neuropsychiatric Interview International Neuropsychiatric Interview.18 Those who met criteria for any psychotic disorder were excluded from participating, and potential women in the control group who met criteria for a mood or anxiety disorder were also excluded. Given the high prevalence of depression and anxiety in persons with chronic pain, endometriosis and chronic pelvic pain participants with comorbid mood or anxiety disorder were included in this study.
Additional exclusion criteria for all participants included severe physical impairment, significant comorbid medical illness that limited physical function, and suicide attempt or substance abuse within 2 years of the study. Women who were pregnant, lactating, or menopausal (defined as no menses for greater than 1 year unrelated to exogenous hormonal suppression) were also excluded from participation.
For the purpose of these analyses, each participant with endometriosis or chronic pelvic pain was then classified into one of the following four categories based on review of the standardized pelvic pain and menstrual history questionnaire (see subsequently) but blinded to the remainder of the study results: “pain-free” endometriosis (⊕EndoØPain), endometriosis with dysmenorrhea (⊕Endo⊕Dysmenorrhea), endometriosis with chronic pelvic pain (⊕Endo⊕CPP), or chronic pelvic pain without endometriosis (ØEndo⊕CPP). The following criteria were used to define each of these categories: chronic pelvic pain was defined as moderate or severe pelvic pain that was 4 or greater on a 0–10 numeric rating scale for a duration greater than 6 months that occurred for at least 14 days of each month, not just limited to the time of menstrual bleeding. Dysmenorrhea was defined as 5–13 days of moderate to severe pelvic pain each month, which generally occurred around the time of menses. Dysmenorrhea was identified as its own distinct category because of recent evidence that otherwise healthy women with dysmenorrhea display evidence of central pain amplification.19 Unless otherwise specified, “pelvic pain” refers to women with either chronic pelvic pain or dysmenorrhea. Women with “pain-free” endometriosis were defined as those who reported 4 days or less of pelvic pain per month. A summary of case definitions for participant subgroups is illustrated in Table 1. The goal was to recruit women for the control group and each subgroup of endometriosis, chronic pelvic pain, or endometriosis and pelvic pain subgroups in a one-to-one ratio.
All participants completed standardized case report forms to assess their demographics, medical and surgical history, medication use, and menstrual pattern. Using The Complex Medical Symptom Inventory, a standardized, diagnostic tool that uses published criteria for the diagnosis of various chronic pain disorders,20 all participants were formally evaluated for all of the following chronic pain syndromes known to be associated with central nervous system pain amplification: fibromyalgia, chronic fatigue syndrome, interstitial cystitis, irritable bowel syndrome, chronic low back pain, chronic migraine headaches, temporomandibular disorder, and vulvodynia. As previously described, potential women in the control group were excluded if they met criteria for any pain syndrome, whereas participants with endometriosis or pelvic pain and comorbid pain syndromes were included in this study.
Participants with endometriosis or pelvic pain completed additional questionnaires to assess the severity, pattern, and characteristics of their pelvic pain and prior treatments for pain. Measurements included numeric ratings (0–10) of pelvic pain severity and unpleasantness during menses and the average number of days with moderate to severe pelvic pain each month (0–30 days). Participants provided written release for review of their most recent operative reports. Operative reports were reviewed by one of the authors with significant expertise in the surgical evaluation of endometriosis and other gynecologic disease. This author was blinded to the study results. Most participants received their surgical diagnosis at another medical institution. The operative findings (presence, severity, and location of endometriosis and pelvic adhesive disease) and surgical procedure performed were documented using a standard case report form. When identified, endometriosis was assigned a stage according to the revised American Fertility Society endometriosis scoring system.21 Surgical biopsy and pathology was documented when available but not required for participation because pathologic confirmation was not routinely performed in all participants.
Quantitative sensory testing was conducted on all participants using the multiple random staircase method previously described by our group.22,23 An apparatus that delivers discrete pressure stimuli was used to determine pressure pain sensitivity at the nondominant thumbnail. Application of calibrated weights to a hydraulic piston produced controlled, repeatable pressure stimuli using water-filled tubing to a second piston with an attached 1-cm2 rubber probe. This system was used to present a series of stimuli to the thumbnail in a predictable, “ascending” fashion, beginning at 0.25 kg/cm2 and increasing 0.25–0.5 kg/cm2 increments up to pain tolerance or to a maximum of 10 kg/cm2. Perceived pain intensity of each pressure was recorded using the Gracely Box Scale, a 0–20 numerical descriptor scale used to measure evoked pain intensity.24
After the ascending series, 36 stimuli were delivered to the thumb at 20-second intervals using the multiple random staircase method. This method is response-dependent; that is, it determines the stimulus intensity (kg/cm2) needed to elicit a specific response. This “adaptive” method automatically adjusts the stimulus intensity applied using each patient's subjective pain rating and a computer program that randomly switches among three different staircase titrations to calculate the pressure intensities required to elicit “faint” pain (0.5 on the Gracely Box Scale), “mild” pain (7.5 on the Gracely Box Scale), and “slightly intense” pain (13.5 on the Gracely Box Scale). The starting points for each staircase are determined from the ascending series. Previous studies have demonstrated that this type of random pressure testing is not influenced by the level of depression or anxiety (“distress”) of an individual.25
To minimize the influence of menstrual cycle variability on study results, all study visits were performed between days 2 and 10 of the menstrual cycle in women who were not using hormonal contraceptives. All patients were asked to refrain from using opioid analgesia within 48 hours of the study visit. Quantitative sensory testing was performed by a research coordinator blinded to the participant subgroup and the remainder of the survey data.
Sample size determination was based on the primary outcome of differences in pressure pain sensitivity in endometriosis–pelvic pain subgroups relative to healthy women in the control group. Based on a previous study by our group in patients with fibromyalgia,26 we estimated a 1.5-kg/m2 difference in pressure to elicit mild pain (standard deviation 2.0) between healthy women in the control group and pelvic pain subgroups. Using a five-group analysis of variance test, the sample size was calculated to be 20 participants for each category to achieve 90% power and α=.05. Analysis was performed using STATA 12.0. All continuous variables were evaluated for normality by using the Shapiro-Wilk statistic. Univariate analysis of data included means, medians, ranges, and standard deviations. Comparison of continuous variables between groups was conducted using analysis of variance or the Kruskal-Wallis test, as appropriate. Categorical data were compared using χ2 test or Fisher's exact test, as appropriate. Linear regression was used to calculate the mean difference and 95% confidence interval of pressure required to elicit faint, mild, and slightly intense pain in patient subgroups compared with women in the control group. Based on bivariate analyses, we evaluated age (years), education (less than 12 years, 12 years, greater than 12 years), and current smoking status as candidate confounders of patient subgroup and pressure pain threshold. Covariates were retained in the final regression model if they changed the effect estimate for the main outcome by 10% or greater when excluded from the model. Age and education status had a modest effect on the main estimate of the main outcome and were therefore included the final model as covariates.
A total of 144 women completed the study between June 1, 2006, and April 31, 2010, including 30 healthy women in the control group and 114 women with chronic pelvic pain or endometriosis. Among participants with chronic pelvic pain or endometriosis, 35 were classified as endometriosis without pelvic pain (⊕EndoØPain), 15 were endometriosis with dysmenorrhea (⊕Endo⊕Dysmenorrhea), 42 were endometriosis with chronic pelvic pain (⊕Endo⊕CPP), and 22 were chronic pelvic pain without endometriosis (ØEndo⊕CPP).
Characteristics of study participants are summarized in Table 2. There were no significant differences in race, body mass index, number of prior pregnancies, or current use of hormonal contraceptives. On average, ⊕EndoØPain participants were older than the other participant subgroups, and participants with chronic pelvic pain (⊕Endo⊕CPP and ØEndo⊕CPP) reported fewer years of education than the nonpelvic pain subgroups. There was no significant difference in the total number of prior abdominal surgeries or the number of surgeries performed for pelvic pain or endometriosis in any of the pelvic pain–endometriosis subgroups. Among women with endometriosis, advanced-stage disease (eg, revised American Fertility stage III and IV disease) was common and ovarian endometriomas were identified in approximately one-third of participants. However, all endometriosis participants had additional peritoneal disease except for three participants (all in the ⊕EndoØPain group) who had ovarian endometriomas without any other pelvic pathology. Most participants with endometriosis had at least partial surgical treatment (ablation or excision) of visible lesions, and only 15.8% had no surgical therapy at all. Among women currently using some form of hormonal contraceptive, all were using either a combined estrogen–progestin method or a progestin-only method. In general, most participants with chronic pelvic pain had clinically severe pelvic pain on most days of the month. Those with dysmenorrhea had a similar intensity of menstrual pain but experienced pelvic pain for an average of 9 out of 30 days per month.
Significantly lower pressure to the thumbnail was required to induce faint, mild, and slightly intense pain in all pelvic pain subgroups relative to pain-free women in the control group (Table 3). Decreased pressure pain thresholds were identified among all subgroups with pelvic pain, including both chronic pelvic pain and those with dysmenorrhea only. However, there was no difference in pressure pain sensitivity when comparing women with endometriosis with patients with pelvic pain without endometriosis (Table 3). Furthermore, among women with chronic pelvic pain, there was no difference in pressure pain sensitivity relative to the presence or severity of endometriosis at the time of the most recent surgery (P=.92; Fig. 1), although the power to detect small differences in this study is limited.
The presence of comorbid pain syndromes in participants with endometriosis or chronic pelvic pain was common and identified in approximately 60% of these women (Table 4). Chronic headaches (migraine or tension headaches) and irritable bowel syndrome were the most frequent comorbid pain conditions. Although the presence of one or more comorbid pain conditions was common in the ⊕EndoØPain group, women with pelvic pain (chronic pelvic pain or dysmenorrhea) were more likely to have a comorbid pain condition than patients with endometriosis without pain (P=.002). Among all participants with pelvic pain, the presence and number of comorbid pain syndromes were not significantly associated with pressure pain sensitivity (P=.77; Fig. 2). Again, the power to detect small differences in this study is limited.
Consistent with our hypothesis, women with pelvic pain demonstrate significantly increased pressure pain sensitivity at a nonpelvic site compared with healthy women in the control group. These findings were identified in all subgroups of pelvic pain participants and did not appear to be related to the presence or severity of endometriosis. Although comorbid pain syndromes were commonly identified in participants with pelvic pain, pressure pain thresholds were also unrelated to the presence or number of other pain syndromes. These findings suggest a generalized upregulation of nociceptive processing in patients with pelvic pain, which is not sufficiently explained by endometriosis and is not simply a marker for having another comorbid pain condition.
The strengths of this study include precise phenotyping of pelvic pain subgroups with various combinations of pain severity and pelvic pathology, the prospective collection of detailed data regarding clinical pain, and the systematic assessment of comorbid pain syndromes using standardized criteria. Disease misclassification was limited by surgical confirmation of endometriosis. Furthermore, our sensory testing paradigm, which uses a stimulus delivered to a remote location from the pelvis, has been shown to be minimally influenced by levels of anxiety or depression.25 Moreover, this sensory testing methodology has been shown to be a valid surrogate measure of central pain amplification. For example, previous trials have shown that sensitivity to experimental pressure applied to the thumbnail, a neutral area not associated with clinical symptoms, correlates with clinical pain,23,27,28 is a marker of widespread pain throughout the body,29 and is associated with augmented brain activity11,12 and elevated levels of excitatory neurotransmitters in key pain processing regions of the brain.30
Our results are consistent with increasing evidence that individuals with various pain syndromes such as fibromyalgia and vulvodynia have a fundamental problem with pain amplification.11,12 Relative to pain-free women in the control group, these individuals report increased pain sensitivity and demonstrate increased neuronal activity in regions of the brain associated with pain perception when exposed to stimuli that healthy individuals find innocuous. Given that amplification of central nervous system pain processing is a common finding across these pain syndromes, these conditions have been referred to as “central pain syndromes.” Although the mechanisms contributing to pain likely occur at various levels of the nervous system, the two mechanisms most described in the literature are loss of descending analgesia and central sensitization.
Hyperalgesia to experimental noxious stimuli has been reported in a few earlier studies of women with endometriosis.14–16 However, interpretation and generalizability of the findings are limited as a result of the small sample size and sparse characterization of the patient population. Unlike these earlier reports, the present study is able to disentangle hyperalgesia from endometriosis, pelvic pain, and comorbid pain disorders by including four patient subgroups with various degrees of pain, pelvic pathology, and comorbid pain disorders.
There are several important limitations of this study. Most importantly, the cross-sectional design of this study precludes our ability to determine whether differences in experimental pain sensitivity are a cause or consequence of the pain experience. Also, the pain testing methods we used cannot identify the specific mechanism of central nervous system pain amplification or the specific interaction between endometriosis and the peripheral and central nervous system. A minor limitation is possible misclassification bias, because not all healthy women in the control group were surgically explored to exclude the diagnosis of endometriosis. Given a 2–9% estimated prevalence of asymptomatic endometriosis, this may alter the diagnostic category for less than three healthy women in the control group.
In this study, pain-free women with endometriosis did not demonstrate hyperalgesia at the thumbnail and exhibited pressure pain sensitivity similar to healthy women in the control group. This finding may help explain why stage of disease and pain severity do not correlate in women with endometriosis. Perhaps the critical variable defining clinical symptoms is an individual's neural processing rather than susceptibility to peripheral inflammation from ectopic endometrial implants. Our group has recently reported that women with pain-free endometriosis show an increase in gray matter volume in the periaqueductal gray, a key structure in the antinociceptive pain regulatory system, which was not found in women with chronic pelvic pain and endometriosis.17 These findings suggest that, despite having significant pelvic pathology that could act as a source of peripheral nociceptive input, this unique subset of pain-free patients with endometriosis does not display evidence of central pain amplification. Given these findings, it is tempting to hypothesize that patients with pain-free endometriosis experience little if any pain as a result of adaptive changes in the brain.
In summary, the current study adds to the growing body of literature that suggests that some women with chronic pelvic pain demonstrate evidence of amplification central pain processing. These findings are present in women with no other identifiable pain disorder and are unrelated to the presence or severity of endometriosis. If chronic pelvic pain is caused in part by central rather than only peripheral factors, this has substantial implications for the evaluation and treatment of women with chronic pelvic pain. For example, it may be that some women will benefit from medical and cognitive therapies aimed at central pain amplification and could avoid repetitive surgeries directed at suppressing or eliminating pelvic structures. Almost certainly, endometriosis and chronic pelvic pain represent highly heterogeneous populations with subgroups that have variable degrees of peripheral and central contributions to pain. Identification of these subgroups may represent a critical step in the development of a personalized, mechanism-based approach that can better guide treatment decision-making for individual patients with chronic pelvic pain.
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