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Andrews J, Yunker A, Reynolds WS, et al. Noncyclic Chronic Pelvic Pain Therapies for Women: Comparative Effectiveness [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Jan. (Comparative Effectiveness Reviews, No. 41.)

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Noncyclic Chronic Pelvic Pain Therapies for Women: Comparative Effectiveness [Internet].

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Results

This chapter presents the results of our systematic review of therapies for women with noncyclic chronic pelvic pain (CPP). We present findings for each Key Question (KQ) beginning with an overview of the content of the literature as a whole, including the range of study designs used, approaches assessed, and participants included. The detailed analysis of the literature provides further discussion and analysis, focusing primarily on those studies that received either a good or fair quality rating.

Studies also are described in more detailed summary tables in the relevant section of text. For information on studies not included in the summary tables, please see the evidence tables in Appendix C; for information on quality scores for each study, see Appendix E.

Overall, we found significant heterogeneity among studies, making it difficult to compare them; this heterogeneity was found in:

  • Definitions of CPP and comorbidities of interest
  • Outcome measures
  • Comparators
  • Duration of treatment
  • Timing and length of followup
  • Study populations.

Article Selection

Of the entire group of 2,081 citations, 623 required full-text review (Figure 2). Of the 623 full text articles reviewed, we retained 39 articles (comprising 36 unique studies) and excluded 584 articles. Reasons for article exclusion are listed in Appendix B.

This figure displays the flow of articles through the review. Our searches retrieved 2,081 nonduplicate citations. We reviewed the full text of 623 articles and included 39 articles, comprising 36 unique studies, in the full review. The full report details reasons for exclusion.

Figure 2

Disposition of articles located for the review. a The total number of articles in the exclusion categories exceeds the number of articles excluded because most of the articles fit into multiple exclusion categories; KQ=Key Question

The 36 unique studies described in this review included 18 randomized controlled trials (RCTs). Table 4 provides an overview of the characteristics of the literature addressing the prevalence of comorbid conditions of interest (KQ1). We considered studies that provided data exclusively for KQ1 (and did not provide data for the other KQs) to be providing cross-sectional prevalence data, regardless of the design of the study.

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Table 4

Overview of noncyclic CPP literature addressing the prevalence of comorbidities of interest.

Table 5 provides an overview of studies addressing KQs focused on outcomes of surgical and nonsurgical treatment approaches (KQ2, KQ3, KQ4) and those addressing the trajectory of care for women with CPP (KQ5).

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Table 5

Overview of noncyclic CPP literature addressing treatment approaches.

Key Question 1. Among women who have been diagnosed with noncyclic/mixed cyclic and noncyclic CPP, what is the prevalence of the following comorbidities: dysmenorrhea, major depressive disorder, anxiety disorder, temporomandibular joint pain disorder, fibromyalgia, irritable bowel syndrome (IBS), interstitial cystitis (IC)/painful bladder syndrome (PBS), complex regional pain syndrome, vulvodynia, functional abdominal pain syndrome, low back pain, headache, and sexual dysfunction?

Overview of the Literature

This section presents results of 26 studies, representing 23 unique study populations, meeting our review criteria and addressing co-morbidities for CPP. Here we review co-prevalence rates for conditions associated with CPP including anxiety, back pain, depression, dysmenorrhea, dyspareunia, fibromyalgia, headache, IC/PBS, IBS, sexual dysfunction, and vulvodynia. We did not locate any articles addressing temporomandibular joint pain disorder, fibromyalgia, complex regional pain syndrome, functional abdominal pain syndrome, or anxiety disorder.

Quality assessments in this section refer to the prevalence quality for the particular comorbidity being discussed. Therefore, an individual study may have different a level of quality for each comorbidity reported. Data regarding the comorbidities most frequently reported in the literature meeting our criteria are reported in tables 5 through 7.

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Table 7

Prevalence of dysmenorrhea in women with noncyclic chronic pelvic pain.

Key Points

  • Prevalence evidence quality for most of the studies was fair or poor.
  • The majority (16/23) of studies reviewed here are observational; 7 are RCTs.
  • Dyspareunia/sexual dysfunction (15 studies), dysmenorrhea (12 studies), and irritable bowel syndrome (10 studies) were the most frequently reported comorbidities.
  • Dyspareunia prevalence in women with CPP ranged from 15 to 88 percent.
  • Dysmenorrhea prevalence in women with CPP ranged from 4 to 100 percent.
  • IBS prevalence in women with CPP ranged from 24 to 39 percent when Rome criteria were used for diagnosis.
  • Understanding comorbidity prevalence in the context of a symptom-based condition like CPP is difficult; at times the same condition may be considered part of the differential diagnosis or considered to be a concomitant condition.

Detailed Analysis

Back pain. Eight studies (Table 6) reported the prevalence of back pain with rates of 1 percent to 88 percent (median 13 percent).13,15,70-76 Studies used varied terminology, including backache, back pain, back problems, low back pain, lumbar disk disease, sacroiliac pain, and muscular back pain. Two studies provided an operational definition. One fair quality study noted magnetic resonance imaging (MRI)-verified pathology.71 The second fair quality study defined sacroiliac pain as back pain with tenderness over either sacroiliac joint and reported 21 women with sacroiliac pain.76 This study also reported patients with lumbar disk disease (n=7) but did not provide a specific definition or diagnostic criteria for it.76

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Table 6

Prevalence of back pain in women with noncyclic chronic pelvic pain.

All of the remaining studies were of poor quality. Three relied on patient report,13,15,74 two on a physician diagnosis,70,72 and one did not report how the diagnosis was made.75 Some of the participants may overlap in two studies70,72 conducted in the same clinic during the same time period; however, it is impossible to determine the extent of overlap.

Depression. Three studies reported the prevalence of depression.70,72,73,77 Prevalence rates of depression ranged from 16 percent to 64 percent.70,72,77 Two studies70,72 of good quality used the Beck Depression Inventory (BDI) to assess for depression. In a prospective cohort study of 370 women referred to a CPP specialty clinic who had CPP, 22 percent had moderate or severe depression defined as a BDI score of 19 or greater70. In a cross-sectional study of 987 women with CPP who were new patients at a pelvic pain clinic, 64 percent had a BDI score of 10 or higher.72 The rationale for selecting the cut point of 10 is not identified. It is possible that some of the women in these 2 studies70,72 are the same because they are from the same clinic during the same time period; however, it is impossible to determine the extent of overlap.

The third study, which was of poor quality, was a placebo-controlled RCT of raloxifene for CPP in 93 women with endometriosis, in which 41 percent of women had a history of “depression” and 16 percent had a history of “depression on hormones.”77 Definitions of depression and hormones are not provided, and no information is given about how this history was obtained.

Dysmenorrhea. Twelve studies (Table 7) reported the prevalence of dysmenorrhea with rates of 4 percent to 100 percent (unadjusted mean 75 percent, median 86 percent).13,15,74,76,78-83 Two studies13,76 were of fair quality. One cross-sectional postal survey reported an operational definition of dysmenorrhea and methods for calculating prevalence among women with CPP who had menstrual periods. Another chart review similarly reported a defitnion.76 The prevalence rate was 81 percent. The other 7 studies were of poor quality.

Dyspareunia. Eleven studies (Table 8) reported the prevalence of dyspareunia.10,13,15,72,74,75,78-81,84 Two of the studies were of fair quality and nine were poor. One fair quality study was a U.S. telephone survey that included 773 women with CPP.10 Of the 432 of those 773 women who were sexually active, 88 percent reported pain during or after sexual intercourse some, most, or all of the time in the past month. The other fair quality study was a postal survey that reported an operational definition of dyspareunia and how prevalence was calculated among women with CPP who were sexually active. The prevalence rate was 41 percent.

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Table 8

Prevalence of dyspareunia in women with noncyclic chronic pelvic pain.

One poor quality study72 reported prevalence for three types of dyspareunia (organic, functional, and mixed) without defining the types and/or clarifying if the rates were overlapping. Excluding this study, the prevalence rates for dyspareunia among women with CPP across all studies ranged from 15 percent to 88 percent (unadjusted mean 54 percent, median 45 percent). See also sexual dysfunction below.

Headache. Three studies from two unique populations reported the prevalence of headache.75,77,85 In an RCT of surgical excision of endometriosis combined with raloxifene or placebo in 108 participants with CPP with and without endometriosis, 79 percent reported recurrent headaches85. Headaches were further classified using International Headache Society (IHS) Criteria. Among all of the 108 women, 67 percent had migraines (defined as four or five of the five major IHS criteria for migraines) and 12 percent had non-migraine headaches. The prevalence quality for this study was poor for headache and good for migraine.85

In an RCT of routine diagnostic laparoscopy versus an integrated approach without routine laparoscopy, 62 percent of 106 women with pelvic pain had headache.75 The definition of headache and method of diagnosis were not provided for this study, which was of poor quality.75

Interstitial cystitis/painful bladder syndrome. Four studies reported the prevalence of IC/PBS.76,86-88 One fair quality chart review included 326 women seeking treatment at a pelvic pain clinic. The study defined IC/PBS as “pelvic pain, pressure, or discomfort related to the bladder, associated with persistent urge to void or urinary frequency, in the absence of infection or other urinary tract disease” and reported a prevalence of 27.8 percent in this population.76 Another fair quality study included 121 women attending a pelvic pain clinic and used response to hydrodistention as a diagnostic criterion. Twenty-one percent of participants were diagnosed with IC.86

In a good quality cross-sectional study of 175 consecutive women at a CPP clinic examining the nature and number of pain diagnoses, 35 percent had IC, defined as a positive response to alkalinized lidocaine bladder instillation or a previous diagnosis of IC from cystoscopy with hydrodistention.87 In a fair quality prospective case series of 162 women with CPP who underwent laparoscopy and cystoscopy, 82 percent had IC defined as greater than 10 glomerulations per quadrant in at least 3 of 4 quadrants.88

Irritable bowel syndrome. Ten studies reported the prevalence of IBS.13-15,70-73,76,86,87,89,90 Two studies with an overlapping population14,15 are reported separately because they used different methods of determining if the women had IBS.

Six studies (Table 9) used the Rome I or II criteria for diagnosis of IBS and reported prevalence rates of 24 percent to 39 percent (unadjusted mean 34 percent, median 35 percent).13,14,72,76,86,87,89 It is possible that some or all of the women in 2 of these studies72,89 are the same because they are from the same clinic during the same time period; however, it is impossible to determine the extent of overlap. Four of these studies13,72,76,87 were of good quality, and 314,86,89 were of fair quality.

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Table 9

Prevalence of irritable bowel syndrome as diagnosed by Rome criteria in women with noncyclic chronic pelvic pain.

Five studies13,15,70,71,90 reported IBS prevalence using methods other than the Rome criteria. In 2 studies, one of good quality13 and one of fair quality,15 women with CPP not exclusively related to menses or sexual intercourse, who had consulted a medical practitioner, self-reported diagnoses they were given. Rates were 26 percent among 149 women who responded to a postal survey in New Zealand,15 and 20 percent among 237 women who responded to a postal survey in the United Kingdom.13 One of these studies13 also reported the percentage of women who met the Rome criteria for IBS, and those results are presented in Table 9.

The remaining three studies70,71,91 were all of poor quality. A prospective cohort study of 370 women evaluated at a pelvic pain clinic reported 37 percent of women had a clinical diagnosis of IBS, defined as the physician indicating the diagnosis was definite or probable.70 It is possible that some of the women in this study70 are the same as women in two of the studies that used Rome criteria72,89 because they are from the same clinic during the same time period; however, it is impossible to determine the extent of overlap. Two studies reported prevalence rates for IBS but did not provide any information about how the diagnosis was made. One of these was an RCT of gabapentin and amitriptyline for CPP among 56 women, of whom 25 percent were reported to have IBS.71 The other was a prospective case series of 106 women with CPP admitted for inpatient psychosomatic treatment, and 1 percent were reported to have IBS.90

Sexual dysfunction. In addition to generalized sexual dysfunction, multiple specific forms of sexual dysfunction were reported including vaginismus, sexual pain disorder, postcoital pain, hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder and anorgasmia, and limits on sexual activity. Five studies addressed one or more of these forms of sexual dysfunction. One of these was of fair quality.92 The remaining four studies were all of poor quality.15,70,72,75 See also the section on dyspareunia above.

Generalized sexual dysfunction. A cross-sectional study of fair quality about sexual dysfunction that included 112 women with CPP used the international classification of female sexual dysfunction (FSD)92 of 4 FSD disorders to classify responses to general assessment questions designed to investigate women's sexual function. Among the 112 women, 70 percent had one or more of the 4 types of female sexual dysfunction (desire, arousal, orgasmic, and sexual pain disorders.).92 In a prospective cohort of 370 women evaluated at a pelvic pain clinic, 76 percent had sexual dysfunction defined as “painful intercourse, decreased frequency, or decreased pleasure resulting from pain.”70 This study was of poor quality.

Hypoactive sexual desire disorder. A cross-sectional study about sexual dysfunction that included 112 women with CPP used the international classification of FSD disorders to classify responses to general assessment questions designed to investigate women's sexual function. Of the 78 women with CPP who had FSD, 54 percent had hypoactive sexual desire disorder.92 The percentage of all of the women with CPP who had hypoactive sexual desire disorder is not reported.

Limits on sexual activity. A New Zealand postal survey about women's health included the open-ended question “Does your pelvic pain affect what you can or cannot do? If so, please describe.” In response to this question, 6 percent of 286 women with CPP said they were “limited in sexual activity.”15

Orgasmic disorder and anorgasmia. A cross-sectional study about sexual dysfunction that included 112 women with CPP used the international classification of FSD disorders to classify responses to general assessment questions designed to investigate women's sexual function. Of the 78 women with CPP who had FSD, 22 percent had orgasmic disorder.92 The percentage of all of the women with CPP who had orgasmic disorder is not reported.

In an RCT of routine diagnostic laparoscopy versus an integrated approach without routine laparoscopy in 106 women with pelvic pain, 42 percent had anorgasmia.75 The definition of anorgasmia (anorgasmy) and method of diagnosis were not provided.

Postcoital pain. In an RCT of routine diagnostic laparoscopy versus an integrated approach without routine laparoscopy in 106 women with pelvic pain, 27 percent had postcoital pain.75 The method of diagnosis and parameters for how long the pain lasted were not provided.

Sexual arousal disorder. A cross-sectional study about sexual dysfunction that included 112 women with CPP used the international classification of FSD disorders to classify responses to general assessment questions designed to investigate women's sexual function. Of the 78 women with CPP who had FSD, 33 percent had sexual arousal disorder.92 The percentage of all of the women with CPP who had sexual arousal disorder is not reported.

Sexual pain disorder. A cross-sectional study about sexual dysfunction that included 112 women with CPP used the international classification of FSD disorders to classify responses to general assessment questions designed to investigate women's sexual function. Of the 78 women with CPP who had FSD, 74 percent had sexual pain disorder.92 The percentage of all of the women with CPP who had sexual pain disorder is not reported.

Vaginismus. Two studies, one prospective cohort and one cross-sectional, reported prevalence of vaginismus.70,72 The studies did not define vaginismus and relied on a clinical diagnosis defined as a physician indication that vaginismus was definite or probable. The rate of vaginismus was 5 percent in both studies.

Vulvodynia. Two fair quality studies76,86 and 2 of poor quality70,87 reported prevalence rates of vulvodynia. A fair quality chart review reported a prevalence of 22 percent for vulvar vestibulitis, defined as vulvar pain with coitus or upon tampon/swab insertion; 2 percent for vulvodynia defined as vulvar pain upon examination; and less than 1 percent for vulvodynia (not defined).76A second fair quality study used a definition of vestibular tenderness to light touch and reported a rate of 19 percent among women seeking treatment at a pelvic pain clinic.86

In a cross-sectional study of 175 consecutive women at a CPP clinic examining the nature and number of pain diagnoses, 5 percent had vulvodynia defined as point tenderness of the vulva including the introitus.87In a prospective cohort study of 370 women evaluated at a pelvic pain clinic, 7 percent had a clinical diagnosis of vestibulitis.70 Clinical diagnosis was defined as a physician indicating the diagnosis was definite or probable, and vestibulitis was not defined.

Key Question 2. Among women with noncyclic/mixed cyclic and noncyclic CPP, what is the effect of surgical interventions on pain status, functional status, satisfaction with care, and quality of life?

This section presents the results of our literature search and findings about outcomes of surgical interventions for the treatment of CPP. The surgical approaches represented in the literature meeting our criteria included diagnostic laparoscopy and laparotomy, hysterectomy, adhesiolysis of intraabdominal and pelvic adhesions, laparoscopic utero-sacral nerve ablation (LUNA), and utero-sacral ligament resection. No studies of approaches such as presacral neurectomy met our criteria.

Overview of the Literature

We identified seven studies addressing surgical approaches; five were RCTs conducted in Europe or New Zealand, and two were prospective cohort studies conducted in the U.S. We rated one study as good93, one as fair,51 and 5 as poor quality.54,70,75,80,94 Three studies compared surgical with nonsurgical or medical approaches for CPP treatment.54,70,75 Three studies compared an active surgical technique, either LUNA or adhesiolysis, with surgical control (diagnostic laparoscopy).51,80,93 One study directly compared two surgical techniques (LUNA vs. utero-sacral ligament resection).94

All studies provided definitions for CPP, although few generalizations can be drawn given the heterogeneity of definitions. All studies accepted patient self-report of pelvic pain or noncyclic pelvic pain as the principal determinant. Only one study specified a minimum degree of severity for pain as a definition component: ≥80 mm on 100 cm visual analog scale (VAS). Three studies incorporated anatomic location in the definition: “midline,”94 within or below the anterior iliac crests,51 or abdomen below the umbilicus, pelvic organs, lower back, vulva, or vagina.70 All but one stipulated a duration of greater than 6 months for chronicity, with one RCT allowing a duration of greater than 3 months.75 One study limited the CPP definition to pelvic pain “unresponsive to common medical treatment.”94

Key Points

  • Of seven studies addressing KQ2, one was assessed as good, one as fair, and five as poor quality.
  • While surgical and nonsurgical approaches to treating CPP both improved pain status, neither was more effective when directly compared in three studies.
  • Laparoscopic lysis of adhesions (with lysis of adhesions limited to those stricturing a bowel loop and a dilated lumen during diagnostic laparoscopy) did not further improve pain scores over diagnostic laparoscopy alone.
  • LUNA was no more effective in improving pain status than diagnostic laparoscopy alone or utero-sacral ligament resection.

Detailed Analysis

Surgical approaches compared with diagnostic laparoscopy. Five RCTs addressed surgical approaches (Table 10). Among studies comparing active surgical techniques to diagnostic laparoscopy, a good quality RCT evaluated laparoscopic lysis of intraabdominal adhesions and randomly assigned patients with visually confirmed abdominal adhesions to either adhesiolysis (n = 51) or no adhesiolysis (n = 47) at the time of diagnostic laparoscopy.93 The study included both men and women; however, over 80 percent of participants were female. The study does not present data for female participants only.

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Table 10

Key outcomes of surgical interventions for noncyclic CPP.

The potential effects of diagnostic laparoscopy in women with CPP have not been fully studied. Improvements following post-diagnostic laparoscopy have been reported but whether these improvements are “real” or “placebo” remains to be determined. Among studies using diagnostic laparoscopy as the comparator to an active intervention, diagnostic laparoscopy was used primarily as a diagnostic tool to try to identify potential pathologic explanations for CPP, and patients were randomized after the diagnostic laparoscopy. In these studies, patients were randomized at the time of surgery, after the diagnostic portion of laparoscopy, to receive additional treatment intervention or not.

After 12 months of followup, both the laparoscopic adhesiolysis group and the diagnostic laparoscopy group reported decreases in 100mm VAS pain scores; however, there was no difference in pain reduction between the 2 groups (p=0.63). The study was powered to measure a difference in the VAS of 35 percent between groups. The mean reduction in the VAS score was approximately 25 to 30 percent for both groups.93 Quality of life (QOL), as assessed using the Medical Outcomes Study SF-36 instrument, improved in both groups with no significant differences between groups (p=0.84). The study did not evaluate functional status or patient satisfaction.

Two RCTs compared LUNA with diagnostic laparoscopy alone.51,80 One of these RCTs was of fair quality study and compared 185 patients with CPP randomized to receive LUNA with 185 patients randomized to receive no additional intervention at the time of diagnostic laparoscopy.51 Pain scores as measured on a 10cmVAS for worst pain level (mean difference in VAS (cm) = -0.02; 95 percent CI [-0.61, 0.65]) or for noncyclic pain(mean difference in VAS (cm) = 0.17; 95 percent CI [-0.4, 0.74]) were not significantly different between groups. There were also no differences in pain scores between treatment groups when analyzed according to pre-determined subsets, including parity (nulliparous, parous), pathology (none, any, endometriosis), or site of pain (central, not central). Using the EuroQOL indices of quality of life, the EQ-5D and EQ-VAS, the authors compared mean differences in scores between the 2 treatment groups and demonstrated no differences in either measure: For EQ-5D, the mean difference was 0.03 (95 percent CI, -0.03 to 0.09), and for EQ-VAS, the mean difference was −0.78 (95 percent CI, -3.9 to 5.4). The study did not assess functional status or patient satisfaction as outcomes.51

The second of the 2 RCTs was a poor quality study comparing LUNA with diagnostic laparoscopy.80 Investigators randomly assigned women with CPP at diagnostic laparoscopy to receive either LUNA or no additional treatment and subclassified participants according to the presence of endometriosis. When patients with no endometriosis receiving LUNA (n= 18) were compared with those not receiving LUNA (n = 32) after 12 months of followup, there were no statistical differences in median change in 10cm VAS score for nonmenstrual pelvic pain (p=0.34) nor in numbers of patients with a greater than 50 percent reduction in VAS score (p=0.8). Similarly, in patients with endometriosis, there were no differences between patients receiving LUNA (n=26) and those not receiving LUNA (n=30) in change in VAS score for pelvic pain (p= 0.58) or numbers of patients with more than 50 percent reduction in VAS score (p= 0.78).

The authors also reported that satisfaction rates in patients with or without endometriosis that receive either LUNA or diagnostic laparoscopy alone did significantly differ; however, the paper provided no description for how satisfaction was assessed or what measure was used. The study did not assess functional status.80

In the only study included in this section of the review to actively compare surgical treatments, Palomba et al. randomly assigned 80 patients with CPP to either LUNA or vaginal utero-sacral ligament resection.94 After 12 months of followup, 36 patients receiving LUNA and 38 patients receiving ligament resection were available for evaluation. Both groups reported improvements in pain severity on 100mm VAS score; however, there was no difference in pain severity between the 2 groups (p= 0.063). The study reported equivalent rates of cure (defined as complete relief of pain or residual CPP not requiring treatment) for both treatment arms (RR=0.9, 95 percent CI [0.78 to 1.33]). The study did not address functional status, patient satisfaction or quality of life as outcomes after surgery.

One poor quality study included women with CPP for whom the initial gynecologic history and physical and psychiatric evaluation did not result in a high index of suspicion for a particular etiology.75 The women were randomized to either a “standard approach” that included laparoscopy, or an “integrated approach” that included somatic or behavioral therapies. Following the laparoscopy, the authors do not report how many of the 49 patients in this group received any subsequent interventions such as physiotherapy or behavioral therapy.

The 57 patients in the integrated approach group received physiotherapy and “equal attention was devoted to possible organic, psychological, dietary, and environmental causes of the pain,” meaning they may have received medical treatments, diet and nutrition advice, or psychosocial therapy. Of the 57 patients in the integrated approach group, 5 eventually underwent a surgical intervention. In this small study population of 57 participants, of whom over 90 percent had undergone prior laparotomy for CPP, performing a laparoscopy as the next step was not as helpful for improving the “general pain experience” or the “disturbance of daily activities” as enrolling the patient in a multidisciplinary program that included physiotherapy. Improvement in general pain experience was reported by 75 percent in the integrated approach group and 41 percent in the surgical approach group. Improvement in disturbance of daily activities was reported by 68 percent in the integral approach group and 37 percent in the surgical approach group, but the authors do not report how improvements in pain experience were determined. Objective multidimensional McGill pain scores were not different between the two groups at the 1-year evaluation.75 There were no differences between treatment arms in improvement in McGill scores after 12 months of treatment (p= 0.38), although “improvement” in McGill scores was not explicitly defined.

Two prospective cohort studies addressed surgical approaches for treating CPP; both studies were poor quality. One study involved participants from tertiary referral centers in the United States and compared medical with surgery therapy for CPP.70 One hundred eighty-one patients receiving nonsurgical or medical therapy, including pharmaceutical therapy (with opioid and nonopioid analgesics, antidepressants, anxiolytics, antineuropathics, sedatives, hormones or anti-inflammatories), physical therapy, psychotherapy or combinations thereof, were compared with 189 patients receiving surgical therapy (including diagnostic laparoscopy, adhesiolysis, endometrial ablation, oophorectomy, hysterectomy, and utero-sacral ablation). After 12 months of followup, both groups reported significantly lower scores on the McGill Pain Questionnaire (both p < 0.001) from baseline, although the improvement was similar in both groups (OR = 1.2, 95 percent CI [0.8, 1.6]). There were no significant differences in change of pain status between the 2 groups, with similar numbers of patients reporting worsened pain (OR = 0.9, 95 percent CI [0.5 to 1.5]), no change (OR = 1.1, 95 percent CI [0.7 to 1.7]), improvement (OR = 0.8, 95 percent CI [0.4 to 1.6]), or resolution of pain (OR = 0.9, 95 percent CI [0.5 to 1.5]. The study did not assess functional status, patient satisfaction with care, and quality of life.

A poor quality cohort study, the Maine Women's Health Study, addressed nonsurgical management of participants with CPP who had undergone prior diagnostic laparoscopy and did not have endometriosis or any other condition that warranted a specific treatment.54 The study reported on 12-month outcomes for 380 patients enrolled in a nonsurgical group compared with 311 patients undergoing hysterectomy in the original Maine Women's Health Study.55 Patients included in the nonsurgical group were those with complete evaluations, including diagnostic laparoscopy, who elected nonsurgical management for leiomyomas, abnormal bleeding or CPP. Only 50 (13 percent) patients with a primary diagnosis of CPP were included in the nonsurgical group. Patients included in the hysterectomy group were those undergoing hysterectomy for non-malignant indications, including leiomyomas, abnormal bleeding, or CPP. Sixty-eight (22 percent) patients undergoing hysterectomy reported a primary diagnosis of CPP. The study also included limited data on a subset of 71 women with CPP only, (without a primary indication of fibroid or abnormal bleeding or other) who underwent nonsurgical management.

Both the surgical and nonsurgical group demonstrated significant improvement in mean number of days with pain per month as determined by structured interview after 12 months of treatment. Those in the nonsurgical group reported a mean reduction of 7 days (from 16/month to 9/month, p < 0.001), while those in the hysterectomy group reported a mean reduction of 18 days (from 19/month to 1/month, p < 0.001). The study did not report comparisons between the two groups.

Functional status, assessed with a validated Activity Index questionnaire, improved in both groups compared with baseline after 12 months of treatment (both p < 0.001), although comparison between the two arms was not performed. Quality of life improvements were assessed via the Mental Health Index, General Health Index, Activity Index, and assessment of positive feelings about symptom status. For all these QOL measures, hysterectomy was associated with significant improvements at 12 months compared with baseline (p < 0.001 for all), while nonsurgical management was only associated with significant improvements in the Activity Index and positive feelings about symptom status (p < 0.001 for both).

The authors report that the likelihood of positive feelings about symptoms status at 1 year of follow-up was significantly increased for participants receiving hysterectomy compared with nonsurgical management (OR=10.45, adjusted for treatment type, age, fertility, parity, education, duration of symptoms, and initial severity of discomfort). Thirty percent of the 50 women with CPP who had nonsurgical management, and who completed the 1-year followup and did not have a hysterectomy during that year, reported positive feelings about symptom relief, compared with 77 percent of 68 women with CPP who had hysterectomy. However, the decision about whether or not to have a hysterectomy was made by the woman and her physician prior to enrolment in the study. Therefore, the study reports that women who self-selected for hysterectomy as a treatment for CPP were more likely to be satisfied with their symptom status after one year than women who self-selected nonsurgical management as a treatment for CPP, with the proviso that the factors that influenced the decision about therapy were not studied.54

Key Question 3. What is the evidence that surgical outcomes differ if the etiology of noncyclic/mixed cyclic and noncyclic CPP is identified after surgery?

We sought evidence that surgical outcomes differed if the etiology of CPP was identified after surgical intervention. We searched for studies of surgical interventions for CPP that reported outcome measures of interest and which indentified at least two groups: those participants who had an etiology identified at the time of the surgical intervention or from surgical histopathology, and those participants who did not have an etiology identified at surgery or from pathology. Surgical approaches included in the literature meeting our criteria are described more fully in the KQ2 section of the report and included laparoscopy, laparoscopic lysis of adhesions, LUNA, and hysterectomy.

We did not identify any studies of surgical procedures in participants with CPP that reported outcomes separately for participants who had an etiology identified compared with those who did not have an etiology identified.

Key Question 4. Among women with noncyclic/mixed cyclic and noncyclic CPP, what is the effect of nonsurgical interventions on pain status, functional status, satisfaction with care, quality of life, and harms?

Overview of the Literature

This section presents results of studies meeting our review criteria and addressing the effectiveness of nonsurgical (pharmacologic and nonpharmacologic) interventions for CPP and harms of such interventions. Seventeen studies meeting our criteria addressed nonsurgical approaches for CPP. Fourteen of these studies were RCTs, and three were prospective cohort studies (Table 11). Only one study was rated as high quality,77,85 three were fair quality,81,95,96 and the balance were poor.54,70,71,75,82,83,97-103 The few placebo-controlled studies77,81,95,103 were typically rated as higher quality.

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Table 11

Key outcomes of hormonal therapies for noncyclic CPP.

Most RCTs investigated hormone-based treatments for CPP. One evaluated antineuropathic agents, and another the neuromuscular blocking agent, botulinum toxin A. Four RCTs examined nonpharmacologic therapies—pelvic floor physical therapy, photographic-enhanced counseling after surgery, pelvic ultrasonography plus counseling, and a standard versus integrated treatment approach. The cohort studies assessed nonsurgical compared with surgical approaches and a hormone-based therapy

Twelve of the 17 studies were performed in Europe, with the remainder conducted in the United States and Australia. Most were conducted at academic institutions. The definition of CPP varied slightly between studies, with several studies not providing a clear definition at all. Most commonly, CPP was defined as moderate to severe pelvic pain for at least 6 months duration, unrelated to menstruation. However, among these studies, the duration ranged between 3 months and 2 years. The required severity of pain varied among studies, with some studies requiring a baseline score on a specified pain index/scale while others relied on patient report only. Several studies (n=9), especially those that trialed hormone-based therapies, also required patients to have a diagnosis of endometriosis. Other than those requiring a diagnosis of endometriosis, studies addressing KQ4 reported no consistent screening for other pain conditions or co-morbidities. A full gynecologic and obstetric history was also rarely reported.

Key Points

  • Only one study met criteria for good quality; this study demonstrated that a selective estrogen receptor modulator (SERM), raloxifene, was associated with a faster return of endometriosis-associated pelvic pain.
  • The majority of studies reviewed here are RCTs, most of which investigate hormone-based therapies.
  • More often, studies compared active versus active interventions; thus is it difficult to determine whether or not both arms are actually demonstrating placebo effect versus treatment effect.
  • Reporting of a systematic evaluation of participants prior to randomization to ascertain the etiology of pelvic pain prior to treatment was limited.
  • Reporting of harms data was very limited among trials; among the placebo-controlled trials, harms were more frequent in the placebo arms.

Detailed Analysis

Hormonal therapies. Hormonal treatments for pelvic pain, with or without an underlying diagnosis of endometriosis, were the most common treatment studied. We identified nine RCTs77,81-83,85,98-100,103 and one prospective cohort study97 involving hormone-based therapies (Table 11). Seven were conducted in Europe82,83,97-100,103 and 2 in the United States77,81,85 with 887 total participants. Three of these used placebo as the control,77,81,103 while the remainder compared two or more active interventions. These included combined estrogen/progesterone contraceptive agents, gonadotropin releasing hormone (GnRH)-analogues, a SERM, and progesterone injection.

Pain reduction was the primary pain-based outcome measured in all studies; however, many tools used to measure this outcome varied. Six studies used a 0–10 point VAS.77,81,82,97,98,100 One study83 utilized a 10 cm VAS and two used a 100mm VAS.99,103 In addition to a VAS, several studies evaluated participants with other pain scales including the McGill Pain Questionnaire, Biberoglu and Behrman scale, and SF-12 or 36. The lack of consistent outcome measures limited our ability to compare outcomes across studies.

One good quality study, one of the few to employ a placebo, evaluated a SERM, raloxifene, looking at its effect on pelvic pain in participants with biopsy-proven endometriosis.77 Compared with placebo, those participants who received raloxifene experienced a return of pain significantly sooner after laparoscopy (OR, 2.81; 95 percent CI,1.41 to 6.19). The effect was so pronounced that the trial was stopped early.

Four studies investigated the effects of the GnRH-analogue leuprolide acetate on pelvic pain. In one fair quality, placebo-controlled study,81 participants randomized to depot leuprolide had significantly greater improvement in pelvic pain scores at the end of 12 weeks of treatment, compared with those randomized to placebo (p<0.001). These participants all had clinically suspected endometriosis. The other three studies were poor quality and compared leuprolide acetate with another active treatment. When compared with gestrinone, a similar GnRH-analogue with mild progestogenic and androgenic effects, both treatment groups experienced significant reduction in pain scores during the treatment period.83 However, the gestrinone group showed overall lower pain scores at the end of followup, compared with leuprolide recipients. The third study evaluated add-back therapy in participants receiving leuprolide acetate for the treatment of endometriosis-associated pain.98 Participants were randomized to leuprolide alone, leuprolide plus daily estradiol and norethindrone, or a daily estroprogestin alone. Participants treated with leuprolide (either with or without add-back therapy) had significantly greater reduction in pain scores compared with those treated with the estroprogestin alone (p<0.01). Those with add-back therapy reported better quality-of-life. The fourth study compared treatment with estroprogestin alone for 12 months with treatment with a GnRH agonist for 4 months followed by with estroprogestin for 8 months for the treatment of endometriosis-associated pain.100 While both arms were effective in the treatment of pain, there was no difference between arms.

Two poor quality studies evaluated monophasic oral contraceptive pills (OCP), both for the treatment of pain associated with endometriosis. The first study99 randomized participants to depot medroxyprogesterone or OCP plus low dose danazol. Both groups reported significant improvement in pain scores, compared with baseline, with no significant between-group difference. In the second study, OCPs were compared with goserelin, another GnRH-analogue.82 During the treatment period, both groups experienced similar reduction of pain, but then had similar return to baseline pain levels once treatment was stopped. There was no significant between-group difference.

One poor quality study evaluated depot medroxyprogesterone and a placebo injection for the treatment of CPP in women with a prior negative laparoscopy103 and reported no significant between group difference. The final hormonal intervention study, also of poor quality, compared two contraceptive delivery methods—the contraceptive vaginal ring (ethinyl estradiol/etonogestrel) and the transdermal patch (ethinyl estradiol/norelgestromin)—for the treatment of endometriosis-associated pain.97 In this cohort study, participants chose their preferred delivery method. The primary outcome of this study was treatment satisfaction, and the study reported no difference between groups in satisfaction with treatment. The study did not report data for the secondary outcome of nonmenstrual pain.

Other pharmacologic therapies. The nonhormonal treatments evaluated include the neuromuscular-blocking agent botulinum toxin A95 and antineuropathic agents gabapentin and amitriptyline.71 In a fair quality, placebo-controlled study, women with 2 years of pelvic pain due to pelvic floor spasm were randomized to injection of the pelvic floor muscles with botulinum toxin A or saline.95 Pain scores, followed for 6 months after injection, were significantly improved in the botulinum group compared with placebo (p=0.009). However, both groups had significantly decreased pelvic floor pressures after 6 months with no significant between-group difference.

In a poor quality anti-neuropathic study,71 participants were randomized to one of three arms: gabapentin daily, amitriptyline daily, or gabapentin plus amitriptyline daily. Each group demonstrated significant improvement in pain from baseline scores; however, pain reduction was significantly greater in participants who received gabapentin (either with or without amitriptyline). Table 12 summarizes key outcomes for these nonhormonal therapies.

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Table 12

Key outcomes of nonhormonal pharmacologic treatments for noncyclic CPP.

Nonpharmacologic therapies. Four trials addressed nonpharmacologic treatments for CPP (Table 13). The first of these was the only one to evaluate pelvic floor physical therapy, described as “distension of painful pelvic structures” as a treatment for pelvic pain.96 In this fair quality study the control group received counseling only. Participants were evaluated at baseline and 2 to 3 weeks after treatment. Those randomized to pelvic floor distention showed significant improvement in pain scores compared with controls (OR, 18.37; 95 percent CI 3.39 to 99.64).

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Table 13

Key outcomes of nonpharmacologic treatments for noncyclic CPP.

Two studies, both of poor quality, addressed practice-based treatment approaches and their effectiveness for overall pain outcomes. The first looked at post-operative counseling after diagnostic laparoscopy, and the effect of showing operative photos from the surgery while discussing findings.101 The addition of photos to counseling had no effect on overall pain scores.

The second study75sought to determine if an integrated treatment approach to pelvic pain (promoting equal attention to organic, psychologic, dietary, and environmental causes of pain) was more effective than the standard approach (excluding organic causes before looking elsewhere) in patients in whom the initial gynecologic history and physical and psychiatric evaluation at the specialty clinic did not result in a high index of suspicion for a particular etiology for CPP. Participants randomized to the integrated approach showed greater improvement in scores in 3 areas: “general pain experience” (p<0.01), “disturbance of daily activities” (p<0.01), and “associated symptoms” (p<0.01). However, there was no significant difference in improvement in McGill pain scores between the integrated and standard approaches.

A fourth poor quality study randomized 100 patients with CPP after a negative laparoscopy to a session of ultrasound and counseling or a “wait and see” approach.102 Participants had similar pain duration, McGill pain scores, and Hospital Anxiety and Depression scale scores at baseline. The study reported that performing an interactive pelvic and transvaginal ultrasound with demonstration, education, reassurance that the findings were normal, and counseling resulted in resolution of pain for 12/46 patients, compared with 4/44 patients in the “wait and see” group.

Medical versus surgical management. Two poor quality prospective cohort studies addressed nonsurgical approaches (Table 14).54,70 In one study, 370 patients in a pelvic pain clinic were followed for a year after treatment either by medical or surgical intervention.70 The choice of treatment was provider-based and solely derived by clinical interaction. Participants were asked to complete baseline questionnaires regarding general medical information, history of abuse, depression screening, and pain assessment. The pain and depression assessments were repeated after one year. Groups were divided into those who received surgical treatment (with or without medical treatment) and medical treatment alone. Though the patient populations and treatment algorithms were highly varied, baseline characteristics were fairly evenly distributed. At the end of one year, improvement in pain was similar in both groups (OR 1.2, 95 percent CI 0.8 to 1.6).

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Table 14

Key outcomes of studies comparing nonsurgical with surgical treatment of CPP.

In the Maine Women's Health Study,54 patients with leiomyomas, abnormal bleeding, or pelvic pain were recruited from private obstetrics and gynecology practices to determine improvement in these conditions when treated with either medical options or hysterectomy. Over the course of their treatment, 118 patients were followed by questionnaire administered at baseline, 3, 6, and 12 months, and included demographic information as well as indices for quality-of-life, functionality, and pain severity. While both treatment groups experienced improvement in pain severity and quality of life, the hysterectomy group showed an even greater degree of change.

Harms of nonsurgical interventions. Among the few placebo-controlled studies addressing nonsurgical approaches to treating CPP,77,81,95 reported harms included depression, amenorrhea, sleep changes, hot flushes, and headache (Table 15). Harms were more frequent in placebo arms compared with either active GnRH agonist or the SERM raloxifene. The numbers of adverse events reported in a placebo (saline) versus botulinum toxin group were roughly equivalent.95

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Table 15

Nonsurgical harms reported in placebo-controlled studies.

Additional harms reported in non-placebo controlled studies included spotting/breakthrough bleeding, changes in libido, vaginal dryness, mood changes, breast tenderness, weight gain, nausea and vomiting, dizziness, skin manifestations, and joint pain.

Key Question 5. What is the evidence for choosing one intervention over another to treat persistent or recurrent noncyclic/mixed cyclic and noncyclic CPP after an initial intervention fails to achieve target outcome(s)?

We sought evidence for choosing one intervention over another to treat persistent or recurrent CPP after an initial intervention failed to achieve the target outcome(s). We did not identify any comparative studies of interventions explicitly noting prior failed interventions and addressing this question.

Ongoing Research

As noted, we also searched U.S. and European trial registries to understand trends in ongoing and recently completed research. We located 8 ongoing or recently completed studies examining interventions including hormonal therapies including GnRh agonists and OCPs, physical therapy techniques, transcutaneous electrical nerve stimulation, acupuncture, and botulinum toxin injection. These studies represent some interventions described in the literature meeting our criteria and also address some interventions not represented. Appendix G contains additional study details.

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