Endometriosis-associated pelvic pain: evidence for an association between the stage of disease and a history of chronic pelvic pain*

Transcription

1 F ERTILITY AND STERILITY Copyright " 1997 American Society for Reproductive Medicine Published by Elsevier Science Inc. Vo!. 68, No. 1, J uly 1997 Printed on acid -free paper in U. S. A. Endometriosis-associated pelvic pain: evidence for an association between the stage of disease and a history of chronic pelvic pain* Dale W. Stovall, M.D.1t Lisa M. Bowser, B.S. David F. Archer, M.D.II David S. Guzick, M.D. t~ University of Pittsburgh School of Medicine, Pittsburgh, Eastern Virgin ia School of Medicine, Norfolk, Virginia, and the Duquesne University, Pittsburgh, Pennsylvania Objective: To track the severity and location of pelvic pain associated with endometriosis throughout the reproductive-age years and to evaluate the associ ation between these pain parameters and the stage of disease. Design: Historical prospective study. Setting: Tertiary care center. Patientls): Forty-eight women with endoscopically staged endometriosis and chronic pelvic pain who had undergone medical and/or conservative surgical therapy. Intervention(s): Each participant was administered a que stionnaire that included a determination of the severity and location of her pain. Main Outcome Measure(s): The stage of disease, the area of the pelvis that contained the bulk of disease, the severity of pain, and the location of the most severe pain were recorded. Result(s): The mean duration from the initial diagnosis until follow-up was 15.7 ~ 3.1 years. Twenty-one (43.8%) subj ects denied an y symptoms of pain on follow-up evaluation. Of the 27 patients with persistent pain, 21 (78%) identified the locati on oftheir most severe pain as being the same as at initial diagnosis. The stage of dis ease at initial diagnosis was significantly associated with a higher degree of pain at follow-up. Conc!usion(s): These data suggest that endometriosis-as sociate d chronic pelvic pain commonly persists throughout the reproductive years and that endometriosis stage is directly related to the persistence of pelvic pain. (Fertil Steril" 1997;68: by American Society for Reproductive Medicine.) Key Words: Endometriosis, pelvic pain, medical therapy, conservative surgical therapy, pregnancy Endometriosis is a chronic disease that is diagnosed in women throughout the reproductive years. Endometriosis is associated with chronic dysmenor- Received Septe mber 1, 1996; revised and accepted, March 26, * Presented in part at the 51st annual Meeting of the American Society for Reproductive Medicine, Seattle, Washington, November 7 to 13, t Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Pittsburgh School of Medicine. t Reprint requests and present address: Dal e W. Stovall, M.D., Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, Univer sity of Iowa School of Medicin e, 200 Hawkins Drive, Iowa City, Iowa (FAX: ; e mail: DALE-STOVALL@UIOWA.EDU) /97/$17.00 PH S (97) rhea, intermenstrual abd ominal and pelvic pain, dyspareunia, back pain, dysuria, and dyschezia. Endometriosis is identified as the cause of pelvic pain in 15% to 32% of women undergoing diagnostic laparoscopy for abdominopelvic discomfort (1, 2). The current staging system for endometriosis is based on the location and bulk of disease (3); however, the extent of endometriosis as defined by contemporary staging methods has not correlated with the degree of pain (4, 5). Depa rtment of Ph ysician Assistant, Duquesne Univer sity. IIDepartment of Obst etrics an d Gynecology, Eastern Virginia School of Medicine. ~ Present address: Department of Obstetrics and Gynecology, Univer sity of Rochester, Rocheste r, New York. 13

2 Numerous therapies, including both medical and surgical approaches, are available to treat women with endometriosis-associated pain. The approved medical therapies for endometriosis-associated pain include danazol and the GnRH agonists. Although these therapies have been shown to be equally efficacious, women participating in these trials were rarely observed for more than 24 months (6-9), with two exceptions (10, 11). In these trials, symptoms recur in at least 50% of patients within 12 months after discontinuing therapy. The options for surgical treatment of endometriosis-associated pain range from conservative laparoscopic treatment to hysterectomy with or without removal ofthe adnexa and peritoneal implants. Clinical trials evaluating the effectiveness of conservative laparoscopic treatment of endometriosis-associated pain demonstrate a similar rate of recurrence as seen in the medical therapy trials (12-14). No randomized clinical trials have compared medical and conservative surgical therapy of endometriosis-associated pain. This study was performed to track the severity and location of pelvic pain associated with endometriosis throughout the reproductive-age years in patients who had undergone either medical or conservative surgical therapy and to evaluate the association between these pain parameters and the stage of disease. Patient Selection MATERIALS AND METHODS Women with endoscopically staged endometriosis and chronic pelvic pain were identified from the records of one of the authors (D.F.A.) from 1979 through The medical records of all patients were reviewed meticulously, with particular attention to the initial history and physical examination, operative reports, and pathology reports. The study population consisted of women who were evaluated for pelvic pain in a reproductive endocrinology practice in a tertiary care center. Some of the patients were infertile. Patients were referred from physicians in the community and from within the department of obstetrics and gynecology; some patients were self-referred. All patients had documentation ofendometriosis implants duringlaparoscopy. Biopsy proofof endometriosis was not required for inclusion in the study. All patients had a history of chronic pelvic pain as defined by pain of at least 6 months' duration. Documentation of the degree, location, and duration of pain from one or more physicians was recorded. Women with a history of pelvic inflammatory disease, uterine leiomyoma, chronic urinary tract infec- 14 Stovall et al, Endometriosis-associated pain tions, chronic gastrointestinal disorders, and affective or psychotic disorderswere excludedfrom the study. Additional exclusion criteria were a body mass index (BMI) of >35% of expected BMI based on height and weight (kg/nr') (15); a history of back or abdominal trauma with persistent disability or pain; menopause or a >6-month history of amenorrhea; and a history of abdominal surgery, except for the diagnosis and/or conservative treatment of endometriosis or for cesarean section. Staging and Treatment Only subjects who had received either danazol or conservative-laparoscopic surgical therapy for endometriosis-associated chronic pelvic pain were included in the study. A 6-month course of danazol (600 to 800 mg four times daily) was administered to patients who were receiving therapy with a clinical endpoint of significant pain relief. The total number of treatment courses per patient was recorded. Medication use was validated in all subjects receiving danazol therapy during follow-up visits, with documentation of side effects and duration of therapy. Conservative laparoscopic surgical therapy consisted of ablation of endometriosis implants, lysis of adhesions, and evacuation and ablation of endometriomas. The total number of laparoscopic surgical treatments per patient was recorded. Patients who received both medical and conservative laparoscopic therapy were included. Each patients was surgically staged at their initial diagnosis. The 1979 American Fertility Society (AFS) classification of endometriosis (16) was used for initial surgical staging purposes. The information from the staging sheet, including the anatomic drawing and the operative report, was used to restage each case using the revised AFS staging system from 1985 (3). The stage ofdisease as calculated by the revised AFS system was used for all analyses. The area of the pelvis that contained the bulk of disease was recorded; for practical purposes, the location of disease was identified as cul-de-sac, ovarian, pelvic sidewall, or bowel. Follow-up To determine the current status of each subject's pain, the participants were administered a questionnaire that included a determination of the intensity of pelvic pain based on a modified pain scale developed by the AFS (17). The severity of pain was categorized as mild, distressing, or excruciating, in accordance with the AFS scale. The intensity of pain at each subject's initial evaluation originally was categorized as mild, moderate, or severe. For purposes of analysis, subjects whose pain was initially Fertility and Sterilityv

3 categorized as moderate or severe were recategorized as distressing or excruciating, respectively. The location of the most severe pain at follow-up was identified as back, midline, lateral, or diffuse. Subjects were asked about other, nondocumented therapies they had undergone. Included were oral contraceptives, progestins, and over-the-counter medications such as nonsteroidal anti-inflammatory medications. The women were asked to verify their medical or surgical treatment for endometriosis and were asked if any nonmedical therapy, such as biofeedback or hypnosis, had significantly decreased their pain. Subjects were asked ifthey had conceived or delivered during the follow-up interval. Analysis Several questions were addressed. First, What is the likelihood that endometriosis-associated pelvic pain will persist throughout the reproductive years? Second, Ifendometriosis-associated pelvic pain does persist throughout the reproductive-age years, does the location of pain vary over time? And third, Are there associations between the stage of endometriosis and the intensity of pain at the initial presentation, the stage of endometriosis and the intensity of pain at follow-up, the location of the bulk of disease (i.e., cul-de-sac, ovarian, pelvic sidewall, or bowel) and the location of the most severe pain at either initial evaluation or at follow-up, and stage of disease and location of pain. A X 2 analysis was used to test for these associations, and a relative risk (RR) was estimated using the Mantel-Haenszel technique when an association was identified. RESULTS A total of 76 subjects with chronic pelvic pain and endometriosis who meet all inclusion criteria, except for the method of treatment, were identified from the medical records. Of these women, 16 (21.0%)had undergone a hysterectomywith or without oophorectomyand 12 (15.8%)had taken cyclic oral contraceptives since their follow-up. After excluding these subjects, a total of 48 white women were eligible for the study. Every subject who met criteria for entry into the study and could be reached by telephone agreed to participate in the evaluation. The average (±SD) age, height, and weight of the subjects was 43.5 ± 3.7 years, 162 ± 4.8 em, and 61.4 ± 4.0 kg, respectively. The average (±SD) age at the time of diagnosis was 26 ± 4.2 years, and the average (±SD) duration from the initial therapy until the current follow-up was 15.7 ± 3.1 years. All subjects had endometriosis-associated pain and 18 (37.5%) of 48 were infertile. Twenty-two patients (45.8%) had undergone medical therapy alone, with a mean (±SD) Table 1 Severity of Endometriosis-Associated Pain in Relation to the Stage of Disease at Initial Presentation" Mild Distressing Excruciating Stage I 3 (21.4) 2 (13.3) 5 (27.8) Stage II 2 (14.3) 8 (53.3) 7 (36.8) Stage III 6 (42.9) 5 (33.3) 3 (15.8) Stage IV 3 (21.4) 0(0.0) 4 (25.1) Total * Values in parentheses are percentages. of 11.8 ± 4.9 months of therapy. Eight patients (16.7%) had undergone laparoscopic therapy alone, and 18 (37.5%) subjects had received a combination of medical and laparoscopic therapy. The 26 women in the laparoscopic or combination therapy groups underwent a mean of 1.3 ± 0.7 laparoscopies after their initial diagnosis. The distribution of the stages of endometriosis was as follows: stage I, 10 subjects; stage II, 17 subjects; stage III, 14 subjects; and stage IV, 7 subjects. Twenty-one (43.8%) subjects denied any symptoms of pelvic, back, or abdominal pain on follow-up evaluation. Of the 27 patients with persistent pain, 21 (78%) identified the location of their most severe pain as being the same as at their initial diagnosis. Upon initial presentation, the severity of pain ranged from mild to excruciating and did not correlate with the stage of disease, as shown in Table 1 (X 2 = 9.15, P > 0.05). Yet, with long-term follow-up, there was an association between the stage of disease and the persistence of pelvic pain with a tendency toward a higher degree of pain in the women with more advanced disease, as shown in Table 2 (X 2 = 16.94, P < 0.01). Women with stage I or II disease were significantly more likely to have persistent pain than were women with stage III or N disease (RR = 12.0; 95% confidence interval [ei] = 2.4% to 68.4%). As the location of the subject's most severe pain tended to remain the same over time, the association between the location of pain at initial diagnosis and the location of the bulk of disease was evaluated (Table 3). Women whose implants were primarily ovarian tended to have lateral pelvic pain. Otherwise, there were no associations between the presence of endometriosis implants in any given area of the pelvis and the location of the subject's most severe pain. There was no association between the stage of disease and the location of pelvic pain (data not shown). There was no association between the type of therapy (medical or surgical or both), and the persistence of pelvic pain at follow-up; however, pregnancy was associated with a decrease in pelvic pain at followup. Of the 21 women who were pain free at follow- Vol. 68, No.1, July 1997 Stovall et ai. Endometriosis-associated pain 15

4 Table 2 Severity of Endometriosis-Associated Pain in Relation to the Stage of Disease at Follow-up" Pain Free Mild Distressing Stage I 7 (33.3) 3 ut» 0(0.0) Stage II 11 (52.4) 6 (27.3) 0(0.0) Stage III 3 (14.3) 8 (36.4) 3 (60.0) Stage IV 0(0.0) 5 (22.7) 2 (40.0) Total * Values in parentheses are percentages. up, 11 (52.4%) had carried at least one pregnancy to :0::20 weeks' gestation. Of the 27 women who had persistent pelvic pain at follow-up, only 5 (18.5%), a significantly lower proportion (X 2 = 6.10, P < 0.05), had carried a pregnancy to :0::20 weeks' gestation. In addition to receiving treatment with danazol and/or conservative surgical therapy, all 48 subjects took some form of analgesic either before or during endometriosis treatment. Narcotic use for relief of pain was documented for 23 (47.9%) patients. Although the percentage of women requiring analgesics to control their pain decreased over time, 36 (75.0%) of the subjects had taken some type of analgesic during one or more occasion between their initial endometriosis therapy and follow-up. Of the 27 women with persistent pain at followup, 11 (40.7%) were using some form of analgesic on a weekly basis, 6 (22.2%) were using analgesics at least once a month but less than once per week, and 10 (37.0%) denied using analgesics for more than 1 month. The most common analgesics used by subjects with persistent pain were nonsteroidal antiinflammatory agents. No subjects admitted to using biofeedback or hypnosis as methods of controlling their pain. DISCUSSION Monitoring women with endometriosis throughout the reproductive-age years provides a window on the natural history of the disease. This study was designed to follow a well-defined, homogenous group of women with endometriosis throughout the reproductive-age years. Each subject had surgically staged endometriosis and chronic pelvic pain and lacked identifiable disease processes that are associated with chronic pain. The potential for heterogeneity in the study population stems from their individualized therapy (medical and/or conservative surgical therapy), varying degree and location of pain, and different stages of disease. Previous reports have demonstrated that after conservative management of endometriosis-associated pain, the discomfort commonly recurs (6-14); however, follow-up in these studies was relatively 16 Stovall et ai. Endometriosis-associated pain short. In this study of women with endometriosisassociated pain who were treated with conservative therapy and who were observed for up to 15 years, we found that 56.2% (27/48) of women with endometriosis-associated pain continued to experience pain throughout most of their reproductive lifetime and that some continue to require analgesics to alleviate their discomfort. One clinical dictum of endometriosis-associated pain has been that the stage of disease does not correlate with the intensity of pain (4, 5). The current staging system for endometriosis (3) uses a weighted point system based on the size, depth, and location of endometriosis implants as well as the presence of either filmy or dense adhesions to produce a cumulative score by which a subject is categorized into one offour stages. Recent data have challenged the clinical opinion regarding the relationship between the stage of endometriosis and the intensity of pain. Koninckx et al. (18) found that deeply infiltrating endometriosis implants, which increase one's cumulative score and stage of disease, were associated with pelvic pain. Perper et al. (19) found an association between the total number of endometriosis implants and the severity of dysmenorrhea. Like previous investigators, we did not find an association between the stage of disease at initial diagnosis and the severity of pain; however, we found that advanced stage endometriosis was associated with an increased risk for persistent pelvic pain. Whereas the current endometriosis staging system includes both endometriosis implants and adhesions, it is difficult to determine whether the association we found between advanced stage endometriosis and persistent pain is a function of the presence of adhesions, implants, or both. Although endometriosis mayprogress in some women (18), a placebo-controlled second-look laparoscopystudy revealed spontaneous regression of endometriosis implants in some asymptomatic women (20). In contrast, adhesions are not likely to regress spontaneously and, therefore, are more likely to be the cause of persistent pain. We separated the location of the bulk of endome- Table 3 Location of Endometriosis-Associated Pain in Relation to the Location of the Bulk of Disease* Cul-de-sac Ovary Pelvic sidewall Bowel Back 2 (l0.5) 0(0.0) 1 (7.7) 0(0.0) Diffuse 8 (42.1) 2 (14.3) 3 (23.1) 2 (100.0) Midline 6 (31.6) 2 (14.3) 7 (53.8) 0(0.0) Lateral 3 (15.8) 10 (71.4) 2 (15.4) o(0.0) Total * Values in parentheses are percentages. Fertility and Sterility"

5 triosis implants into four categories to determine if an association exists between the location of endometriosis implants and the location of the subject's most severe pain. Recently, Vercellini et al. (21) reported that the presence of vaginal endometriosis implants was frequently associated with severe deep dyspareunia. Of the 14 women whose disease was primarily ovarian, 10 (71.4%) experienced primarily lateral pain. Otherwise, there were no clear associations between the presence of endometriosis implants at any other anatomic site and a given location of pain. Pain perceived by an insult to the peritoneum is mediated through afferent sensory fibers. These afferent nerve fibers sense pain in relation to location and intensity in a well-defined manner. Therefore, one would have expected both culde-sac and pelvic sidewall implants to cause pain that was confined to a similar anatomic location, and yet this was not the case. Conversely, the pelvic organs receive their sensory innervation from sympathetic or parasympathetic visceral nerves that sense pain in an ill-defined manner. Nevertheless, ovarian implants tended to cause more clearly defined lateral discomfort. This paradox may be explained by the fact that the pathophysiology by which endometriosis causes pain is not related to the infiltration of a given organ or tissue but is the result of a more global peritoneal effect. We were unable to demonstrate an association between any type of conservative therapy and the persistence of pelvic pain at follow-up. The power of our study, however, to find a 50% increase in the relief of pelvic pain (e.g., 50% to 75%) with an Q' of 0.05, was limited (35%). Some data suggest that pseudopregnancy hormonal regimens induced by estrogens and progestogens are an effective treatment for endometriosis-associated chronic pelvic pain (22). Although anecdotal reports of improvement in endometriosis-associated pelvic pain after pregnancy are ubiquitous, there are little data to support the hypothesis that pregnancy has a long-term effect on endometriosis-associated pelvic pain. In this study, the proportion of women who had carried at least one pregnancy to at least 20 weeks' gestation was significantly greater in the group ofwomen who were pain-free at follow-up compared with the group of women who had persistent pain at follow-up. This data suggest that pregnancy is associated with an improvement in endometriosis-associated pelvic pain. Alternatively, one could argue that pelvic pain is somehow related to infertility and, therefore, women with less pain were more likely to conceive. The study population included a very homogenous group of women. In general, the study participants were healthy nonobese women. Each participant was white, presented with pain in her second decade of life, and was diagnosed with endometriosis via laparoscopy. None of the women elected to undergo radical surgical therapy for her endometriosis or had abdominopelvic pathology, such as dysfunctional uterine bleeding, uterine leiomyomata, pelvic inflammatory disease, or chronic gastrointestinal disease. Excluding women from the study with chronic medical illnesses that are associated with pelvic, abdominal, or back pain was important to eliminate confounders that would have impaired our assessment of the long-term association between endometriosis and pain. Furthermore, the women who participated in the study lead relatively nontransient life styles, which made long-term follow-up possible. Although none of the women in this study elected to undergo hysterectomy or any other nonconservative therapy for their endometriosis-associated pelvic pain, a significant number continued to experience pain for many years. 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