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Research Protocol – Oct. 19, 2010

Comparative Effectiveness of Treatments for Noncyclic Chronic Pelvic Pain in Women

Formats

On November 15, 2010, December 8, 2010 and February 4, 2011, several amendments were made to this protocol. To view these amendments, please see the section titled “Summary of Protocol Amendments.

Table of Contents

Background and Objectives for the Systematic Review

Background

Chronic pelvic pain (CPP) in women is a commonly occurring and poorly understood condition. Little consensus on the definition of the condition exists, with the duration of pain noted in published studies varying from three to greater than six months and the location of pain and pathology largely unspecified.1 The American College of Obstetrics and Gynecology (ACOG) defines CPP as “non-cyclical pain of at least six months' duration that appears in locations such as the pelvis, anterior abdominal wall, lower back, or buttocks, and that is serious enough to cause disability or lead to medical care.”2 The causes of CPP are not well understood and may be associated with gynecologic (e.g. endometriosis) and non-gynecologic (e.g. irritable bowel syndrome) conditions. Diagnosis of an underlying cause is complicated as pain is rarely associated with a single underlying disorder or contributing factor;3 Howard outlined over 60 diseases/conditions associated with CPP.3 Frequently diagnosed etiologies include endometriosis, adhesions, irritable bowel syndrome, and interstitial cystitis/painful bladder syndrome;2-3 however, a definitive diagnosis is often not made. One retrospective study from the UK reports that over 25% of women with CPP never received a definitive diagnosis in nearly four years of follow-up.4 Diagnosis is often ultimately dependent on surgery or other invasive procedures. A thorough patient evaluation including pain history and mapping is a critical step in determining potential etiology and an initial therapeutic course and in establishing a rapport between the clinician and patient.5-6 Organizations such as the International Pelvic Pain Society have developed intake questionnaires to facilitate accurate history-taking.

Given the lack of established definitions for CPP, prevalence has been variously estimated. The prevalence of non-cyclic pelvic pain (i.e. not occurring in concert with menstruation or in a temporal pattern) was estimated to range from 4.0% to 43.4% in a systematic review of worldwide prevalence.7 Earlier prevalence estimates put the US rate at 14.7%.8 Annual costs of outpatient visits in the US have been estimated at over $880 million,8 and the condition carries a significant quality of life burden in terms of sexual functioning, depression, fatigue, and limitations and disability associated with pain.8-9

Treatment is typically focused on ameliorating symptoms and varies from pharmacologic therapies including narcotic and non-narcotic analgesics; anticonvulsants; serotonin reuptake inhibitors; botulinum A toxin injections; and hormonal therapies including oral contraceptives, progestogens, and gonaotropin-releasing hormone agonists (GnRH). Other medical therapies include aromatase inhibitors and combination therapies. Surgical interventions, which may be performed laparoscopically or in open procedures, include hysterectomy (with or without oophorectomy or salpingooophorectomy), uterosacral nerve ablation (UNA), presacral neurectomy, lysis of adhesions, and utero-sacral ligament resection. Behavioral therapies include biofeedback, psychotherapy, cognitive behavioral therapy (CBT), and support groups. Among allied health approaches, physical therapy, dietary modification, and exercise therapy have been reported for treating CPP. Complementary and alternative modalities include hypnosis, herbal medicine, massage, acupuncture, meditation, and stress reduction approaches.

Scan of the Literature

A significant body of literature reports on aspects of CPP treatment in women; initial searches in the PubMed system identified more than 3,000 papers published since 1980; after eliminating case reports and non-original research, over 1,600 studies remain with an estimated 15% relevant to CPP therapies in women. The literature reports a variety of interventions in the medical/surgical, behavioral, allied health, and complementary arenas aimed at treating CPP or underlying conditions such as endometriosis, dysmenorrhea, or adenomyosis, with few randomized controlled trials (RCTs).

A recent Cochrane review of 14 RCTs of interventions for chronic pelvic pain (excluding studies of patients with primary diagnoses of dysmenorrhea, pelvic inflammatory disease (PID), irritable bowel syndrome (IBS), or endometriosis) noted that the range of effective therapies for CPP is limited and recommendations are based largely on single studies.10 A recent narrative review11 similarly concluded that few treatment modalities have demonstrated benefit for CPP symptoms. Evidence supports the use of oral medroxyprogesterone, goserelin, adhesiolysis for severe adhesions, and a multidisciplinary treatment approach for patients without a specific diagnosis. Less supporting evidence is available for oral analgesics, combined oral contraceptive pills, GnRH agonists, intramuscular medroxyprogesterone, trigger point and botulinum A toxin injections, neuromodulative therapies, and hysterectomy.11 ACOG guidelines from 2004 note good and consistent scientific evidence (level A) for combined oral contraceptives and NSAIDs for dysmenorrhea pain; GnRH agonists for suspected and confirmed endometriosis- and IBS-associated pain; daily, high dose progestins for pain associated with endometriosis and pelvic congestion syndrome; presacral neurectomy for centrally located dysmenorrhea; and adding psychotherapy to medical approaches.2

Summary

CPP is a common and broadly defined condition. Definitive diagnosis (of the etiology of CPP), when achieved, is largely made post-operatively, and multiple interventions are used empirically in clinical practice to manage potential etiologies and to treat pain symptoms. The condition is frequently complicated by co-morbidities including depression, anxiety, fibromyalgia, and other idiopathic pain disorders, and treatment must target symptoms across a given patient’s conditions. Existing literature cites a range of treatment options for women with CPP, many of which have not been tested in rigorous studies.

Key informants noted a critical need to understand how to prioritize treatment for women with non-cyclic or mixed cyclic/non-cyclic CPP, in particular, how to provide patients with balanced information about probable outcomes given a specific course of treatment. Evidence about pathways of care and how to treat unresolved chronic pelvic pain once treatment avenues have been tried is largely lacking. It is clear that there is a real need for synthesized research that evaluates the evidence base for various treatments and identifies gaps in the current literature that may drive the research agenda.

FDA Approved Treatments

While no surgical or non-surgical treatments have been specifically approved for CPP, multiple treatments have been approved for the treatment of pain and other symptoms associated with CPP; pharmacologic agents include analgesics, hormonal therapies, serotonin reuptake inhibitors, anticonvulsants, antidepressants, aromatase inhibitors, neuromuscular blocker agents, and combination therapies. Selected specific agents are listed below (see PICOTS). Numerous surgical approaches have been advocated, including preservative: lysis of adhesions, uterosacral nerve ablation; injection of perineum; and excisional: hysterectomy, oophorectomy, and excision of peritoneum. Other treatment categories include behavioral, physical therapy, and integrative health measures.

The Key Questions

Introduction

For the purposes of this review, we will define chronic pelvic pain as pain of more than three months duration, localized to the anatomic pelvis (lower abdomen below umbilicus) of sufficient severity to cause functional disability or cause the patient to seek medical care; this three month timeframe is in alignment with published definitions of chronic pain,12-13 including that of the International Association for the Study of Pain, which defines chronic pain as “current continuous or intermittent pain or discomfort which has persisted for more than three months, with recent or frequent seeking of treatment or use of analgesic medication.”13

We developed the key questions for this review based on key informant and expert input. Questions were posted to the AHRQ web site for public comment for approximately four weeks. Comments received on the posted key questions will be used in framing the report.

Comments generally related to the need to understand the association of patient history factors (pregnancy and birth history, history of pelvic surgery, etc.) and chronic pelvic pain, including how factors may modify therapeutic choices. We will capture such factors as presented in the literature meeting our criteria where studies attempt to identify differences in outcomes by medical history.

We explored the potential of developing a separate key question to address patient history and effects on CPP with our Technical Expert Panel (TEP). The team and TEP agreed that our approach to such factors (capturing as possible in data extraction where such factors were associated with outcomes) is sufficient and that a specific key question addressing such factors is not necessary.

We also clarified the wording of Key Question 3 based on public comments and our intention to stratify our assessment of the effectiveness of surgical treatment by diagnosis where such information is available based on a comment addressing the need to understand surgical alternatives and outcomes for specific diagnoses.

Additional public comments related to the need to clarify that the review will address specific surgical and non-surgical therapies such as vulvar vestibulectomy and herbal medicine. Our intention is to include studies of any intervention focused on the management of CPP and meeting our inclusion/exclusion criteria. Other comments dealt with elements of etiology, diagnosis, efficacy, and practice structures and are best suited to be addressed through original research or the development of practice guidelines that could result from this review.

After discussion with our TEP following the public posting of the key questions, we further refined the questions to:

  • articulate a discrete list of comorbidities of interest in KQ1
  • include dysmenorrhea as a comorbidity of interest in KQ1
  • clarify that KQ1 includes only women presenting for treatment for a diagnosis of CPP
  • specify outcomes of interest in KQ2 and KQ4 in line with our discussion of outcomes in the PICOTS for the review

The following key questions represent a consensus of input we received on the questions and team opinion.

Key Questions

Question 1. Among women who present for treatment for a diagnosis of Chronic Pelvic Pain (CPP), what is the prevalence of the following co-morbidities: dysmenorrhea, major depressive disorder, anxiety disorder, temporomandibular joint pain disorder, fibromyalgia, irritable bowel syndrome, interstitial cystitis/painful bladder syndrome, complex regional pain syndrome, vulvodynia, functional abdominal pain syndrome, low back pain, headache, and sexual dysfunction?

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

Question 3. What is the evidence that surgical outcomes differ by whether an etiology for CPP is identified after surgery?

Question 4. Among women with CPP, what is the effect of non-surgical interventions on pain status, functional status, satisfaction with care, quality of life, and harms?

Question 5. What is the evidence for choosing one intervention over another for treating persistent or recurrent CPP after initial intervention (which failed to achieve target outcome(s))?

PICOTS

Population

  • Adult women with non-cyclic or mixed cyclic/non-cyclic chronic pelvic pain undergoing surgical or non-surgical treatment (excluding those studies whose participants’ primary diagnoses include conditions other than CPP)

Interventions

  • Surgical interventions (via laparotomy or laparoscopy, and with or without oophorectomy, salpingo-oophorectomy) including
    • Hysterectomy
    • Presacral neurectomy
    • Uterine suspension
    • Utero-sacral nerve ablation (UNA)
    • Utero-sacral ligament resection (ventrosuspension)
    • Lysis of adhesions
    • Ablation of endometrial implants
    • Resection of peritoneum (partial)
    • Diagnostic laparoscopy (only)
    • Venous blockage (surgical approach or via interventional radiology)
  • Non-surgical interventions including:
    • Medical therapies
      • Analgesics
        • Non-narcotic including NSAIDs. Agents include: acetaminophen/Tylenol; pregabalin/Lyrica; diclofenac/Cataflam, Voltaren, Zipsor; celecoxib/Celebrex; ibuprofen/Advil, Motrin; naproxen/Aleve; indomethacin/Indocin; ketorolac/ Toradol
        • Narcotic including opioids. Agents include fentanyl/Duragesic; acetaminophen+codeine/Tylenol with Codeine; butorphanol/Stadol; dihydrocodeine/Synalgos; hydrocodone and ibuprofen/Reprexain; hydromorphone/Dilaudid; levorphanol/Levo-Dromoran; meperidine/Demerol; morphine+naltrexone/Embeda; nalbuphine/Nubain; oxycodone/OxyContin, OxylR, Roxicodone; oxycodone+acetaminophen/Endocet, Percocet, Roxicet, Tylox, Magnacet, Primalev; oxycodone+aspirin/Percodan, Endodan; oxycodone+ibuprofen/Combunox; oxymorphone/Opana; pentazocine/Talwin; propoxyphene/Darvon; tapentadol/Nucynta; tramadol/Ryzolt, Ultram; hydrocodone/Vicodin, Lortab, Vicoprofen
      • Hormonal therapies
        • Contraceptives including estrogen and progestin combinations—agents include ethinyl estradiol+levonorgestrel/Alesse, Nordette, Seasonale, Seasonique,Triphasil, Portia, Jolessa, Lessina,Levora; ethinyl estradiol+desogestrel/Ortho-cept, Apri, Cyclessa; ethinyl estradiol+drospirenone/Yasmin, Yaz; ethinyl estradiol+etonogestrel/NuvaRing; ethinyl estradiol + norelgestromin/OrthoEvra; ethinyl estradiol+norethindrone/Tri-Norinyl, Junel, femhrt, Ortho-Novum,Ovcon, Tilia; ethinyl estradiol+norgestimate/Orth-Cyclen, Ortho-TriCyclen; ethinyl estradiol+norgestrel/Lo Ovral, Cryselle; Etonogestrel/Implanon; Levonorgestrel IUCD/Mirena; medroxyprogesterone/Depo-Provera; norethindrone/Aygestin, Camila, Jolivette; norethindrone+mestranol/Necon, Norinyl, Ortho-Novum
        • Progestogens including medroxyprogerterone/Depo-Provera, Provera; norethindrone/Aygestin, Camila, Jolivette, Ortho Micronor
        • GnRH agonists (with or without add back estrogen therapy). Agents include buserelin/Suprefact; goserelin/Zoladex; leuprolide/Lupron; nafarelin/Synarel
        • Androgens. Agents include danazol/Danocrine
        • Selective progesterone receptor modulators (SPRM). Agents include mifepristone/Mifeprex; ulipristal acetate/Ella
        • Selective estrogen receptor modulators (SERM). Agents include tibolone/Donna, Libriam; ranitidine/Evista; clomiphene/Clomid; tamoxifen
      • Anticonvulsants. Agents include gabapentin/Neurontin; pregabalin/Lyrica
      • Serotonin Reuptake Inhibitors. Agents include citalopram/Celexa; escitalopram/Lexapro; fluoxetine/Prozac, Sarafem, Selfemra; fluvoxamine/Luvox; olanzapine+fluoxetine/Symbyax; paroxetine/Paxil, Pexeva; sertraline/Zoloft
      • Tricyclic antidepressants. Agents include amoxapine/Asendin; desipramine/Norpramin; nortriptyline/Pamelor; protriptyline/Vivactil; amitriptyline/Elavil; clomipramine/Anafranil; doxepin/Prudoxin, Sinequan,Zonalon; imipramine/Tofranil; trimipramine/Surmontil
      • Serotonin/Norepinephrine Reuptake Inhibitors. Agents include duloxetine/Cymbalta; desvenlafaxine/Pristiq; milnacipran/Savella; venlafaxine/Effexor
      • Anesthetic injections. Agents include lidocaine/ Xylocaine; bupivacaine/Marcaine, Sensorcaine
      • Aromatase inhibitors. Agents include anastrozole/Arimidex; letrozole/Femara
      • Neuromuscular Blocker Agents. Agents include onabotulinumtoxin A/Botox; abobotulinumtoxinA/Dysport
      • Combination therapies (e.g. oral contraceptive+aromatase inhibitor)
    • Behavioral interventions
      • Psychotherapy
      • Cognitive behavioral therapy
        • Self-administered
        • Professionally administered
      • Counseling and support groups
    • Physical therapy interventions
      • Physiotherapy
      • Biofeedback
      • Exercise therapy
    • Complementary and alternative
      • Dietary restrictions
        • Example: low oxalate diet
      • Dietary additions
        • Example: probiotics
      • Massage
      • Acupuncture
        • TENS, electrical stimulation
      • Herbal medicine
      • Magnetic field therapy


Co-interventions include any surgical or non-surgical modality received along with the primary treatment.

Comparators

  • Surgical compared with non-surgical approaches
  • Non-surgical approach compared with non-surgical approach
  • Surgical approach compared with surgical approach
  • Combination approaches


Outcomes and adverse events

Primary outcomes

  1. Pain status
    1. reduction in pain
      1. at least 50% pain reduction
      2. at least 30% pain reduction
      3. proportion below 30/100 mm (no worse than mild pain)
      4. patient global impression (very much improved)
    2. recurrence of pain
      1. percent with recurrence at a selected interval
      2. interval between resolution of pain and recurrence of pain
    3. subsequent intervention for the unresolved or worsening pain (if reported within longitudinal study)
  2. Functional status (resolution/improvement of functioning)
    1. Measured with the same instrument before and after the intervention and in intervention group and comparator group
    2. Activities of daily living
    3. Sexual functioning (if this was affected by the pain)


Secondary outcomes

  1. Patient satisfaction with pain management
  2. Quality of life
  3. Harms, Adverse events
    1. Withdrawal due to adverse event
    2. Serious adverse events
    3. Death (including suicide)


Timing

  • Short-term outcomes will be considered as those that occur ≤ 12 weeks


Setting

  • Settings include any clinical setting

Analytic Framework

Figure 1: Analytic Framework for Therapies for Women with Chronic Pelvic Pain*

This figure illustrates how women with chronic non-cyclic or mixed cyclic/non-cyclic pelvic pain enter into treatment choices. Treatment choices include surgical or non-surgical approaches and may lead to outcomes including changes in patients satisfaction, quality of life, need for pain medication, unresolved pelvic pain, or harms/adverse effects. In addition, outcomes may vary by diagnosis in those patients receiving a confirmed diagnosis for the etiology of their chronic pelvic pain.

*We refined this framework after the public posting of the key questions to align more closely with frameworks included in recent AHRQ reviews. Specifically, we removed contextual factors that may affect therapeutic choices or outcomes (e.g., provider training, socioeconomic status, health literacy, etc.) and will discuss such factors in the text of the review.

Methods

A. Criteria for Inclusion/Exclusion of Studies in the Review

Table 1 lists inclusion/exclusion criteria developed based on our understanding of the literature developed during the topic refinement phase, input from content experts, and established principles of methodological quality.

We set a cut-off level for study size for inclusion of RCT and prospective studies in the review at a minimum of 50 participants. We determined this level based on considering the following factors:

  • Prevalence: varies by population, to maximize acceptable study size, we will use 100%
  • Loss to follow-up: varies by study, to maximize acceptable sample size, will assume 0%
  • Type I Error, alpha level, or p-value: we will set at standard of 5%
  • Clinical effect size anticipated / clinically relevant: 30% minimum; 50% is a better benchmark (for reduction of pain outcome with a validated measure)
  • Placebo effect: known to be 30-50% in chronic pain studies
  • Desired statistical power level: set at standard 0.80
  • Statistic: use two-tailed z-test and t-test for sample size
  • Sample size: for an RCT with 2 groups, with 100% meeting criteria for CPP, with 0% loss to follow-up
  • Null hypothesis of effect size of 50%:need 64 per group, 128 total sample size would be smallest acceptable
  • Null hypothesis of effect size of 30%: need 176 per group, 352 total sample size would be smallest acceptable

Therefore, a conservative lower limit for sample size can be set at 50, to account for potential meta-analyses aggregating smaller trials at sufficient power to produce a confidence interval that excludes 1.

We will limit the review to studies published between 1990 and the present as laparoscopic techniques began to be used and reported extensively in the 1990s; the 1990 timeframe is also contemporaneous with the introduction of medications such as serotonin reuptake inhibitors used to treat CPP. We will also exclude those studies primarily focused on common co-morbidities of CPP including irritable bowel syndrome (IBS) and painful bladder syndrome (PBS) as well as those focused on pain primarily on cancer pain or pain during pregnancy. We will also focus the review on studies published in English given a lack of translation resources.

In addition, for KQ1 we will include only studies that report the selected comorbidities and include at least 100 participants.

To ensure that harms/adverse events data which may be presented in descriptive studies are included, we will include case series with ≥ 100 participants (adult women with CPP) and presenting non-surgical harms data. We will also extract non-surgical harms from papers included in the review.

We reviewed these criteria with the TEP and clarified our approach to our harms based on TEP feedback. We will extract non-surgical harms data from studies included in the review; we will supplement our discussion of harms, especially surgical harms, which are well-reported in published syntheses and overview materials, with reports of harms from relevant published systematic reviews. We also corrected a misalignment between our discussion of outcome measures and our requirement of the use of validated outcome measures as an inclusion/exclusion criterion. We will now require that studies include at least one outcome measure (regardless of validation) for an outcome detailed in our PICOTS (pain status, functional status, harms).

Table 1: Inclusion/Exclusion Criteria
Category Criteria
Study population Adult women (≥ 18 years of age) with non-cyclic or mixed cyclic/non-cyclic chronic pelvic pain undergoing surgical or non-surgical treatment
Time period 1990—present
Publication languages English only
Admissible evidence (study design and other criteria) Admissible designs
  • Controlled trials, prospective trials with historical controls, prospective cohort studies with N ≥ 50
  • Case series with N ≥ 100 and harms or prevalence data relevant to the KQs
Other criteria
  • Original research studies that provide sufficient detail regarding methods and results to enable use and adjustment of the data and results
  • Patient populations must include adult women (≥18 years of age) being treated for CPP; studies with a primary focus on co-existing conditions (vulvodynia, IBS, etc.) or on cancer pain or pregnancy-related pain will be excluded
  • Studies must include at least one outcome measure of an outcome listed in the PICOTS
  • Studies must address one or more of the following for CPP:
    • Treatment modality aimed at modifying CPP symptoms
    • Short- and long-term outcomes (including harms) related to treatment for symptoms of CPP
  • Relevant outcomes must be able to be extracted from data presented in the papers
  • Sample sizes must be appropriate for the study question addressed in the paper
  • Studies addressing KQ1 must include diagnosis of comorbidities using at least one validated tool for that co-morbid condition (exception: if no validated tool exists for that condition or existed at the time the study was published)

B. Searching for the Evidence: Literature Search Strategies for Identification of Relevant Studies to Answer the Key Questions

Search the Literature. To ensure comprehensive retrieval of relevant research into therapies for women with chronic pelvic pain (CPP), our approach to the literature will include four key databases: the PubMed medical literature database, the PsycINFO psychology and psychiatry database, the Cumulative Index of Nursing and Allied Health Literature (CINAHL), and the EMBASE Drugs & Pharmacology database. Search strategies in each of these databases will focus specifically on terms related to CPP, including keywords and subject terms, and a combination of subject terms and/or keywords representing therapeutic interventions (e.g., pelvic pain, endometriosis, therapy, therapeutics, etc.).

We will update the search quarterly during the abstract and full-text review stages, adding relevant references to the pool of articles under consideration as needed. We will also update the search upon submission of the draft report and add relevant references as needed while the draft report is undergoing review. We will also incorporate references meeting our inclusion criteria or of particular relevance for background sections that may be brought forward by public/peer reviewers.

We will employ additional searches of the reference lists of recent existing systematic reviews or meta- analyses of CPP in women; the investigative team will also scan the reference lists of articles undergoing full text review for citations potentially meeting inclusion criteria.

Search for Grey Literature and Regulatory Information. Approaches for managing pelvic pain often include initial treatment with widely-used drugs such as ibuprofen and oral contraceptives to attempt to elucidate an underlying cause. Broad searches for grey literature/regulatory information on such commonly-used drugs would likely return little relevant material.

Our approach to searching for grey literature/regulatory information therefore included consulting the TEP to determine those drugs or devices for which searches would be likely to provide relevant information about harms or other outcomes. The TEP advised that we prioritize by focusing on hormonal therapies, which are commonly used and have a number of known side effects (e.g. provera, lupron, mirena); the team also noted that drugs beginning to be used in women with CPP, including aromatase inhibitors, should also be investigated. Based on TEP and team input, we will request additional information on the following:

  • Medroxyprogerterone/Depo-Provera, Provera
  • GnRH agonists (with or without add back estrogen therapy). Agents include buserelin/Suprefact; goserelin/Zoladex; leuprolide/Lupron; nafarelin/Synarel
  • Selective progesterone receptor modulators (SPRM). Agents include mifepristone/Mifeprex; ulipristal acetate/Ella
  • Selective estrogen receptor modulators (SERM). Agents include tibolone/Donna, Libriam; ranitidine/Evista; clomiphene/Clomid; tamoxifen
  • Aromatase inhibitors. Agents include anastrozole/Arimidex; letrozole/Femara
  • TENS, electrical stimulation.

We will incorporate relevant information from grey literature searches into the review as appropriate.

Develop Data Collection Forms. We will develop data collection forms for abstract review, full text review and data extraction. Abstract review forms will contain questions about primary exclusion/inclusion criteria. Full text review forms are somewhat more detailed and intended to assist in a) identifying studies that meet inclusion criteria and b) conducting an initial sort of studies into appropriate key questions. Finally, data extraction forms will collect those data necessary for evidence tables and synthesis. We anticipate that these data will include studies’ operational definition of CPP and those patient history factors (as discussed on page 3) associated with our outcomes of interest.

Prior to data collection, we will develop, informed by clinical expertise, lists of potential confounders and effect modifiers (e.g., simultaneous therapies/synergistic effects, comorbidities/co-existing conditions, socio-cultural context, etc.) and expected outcomes for the data extraction form. The form also will include an opportunity to report on funding source.

After reviewing a sample of relevant articles, the Methods and Content Leads will design the data collection forms and test them on multiple articles before initiating each stage of data extraction. We expect that the data collection forms will undergo several revisions based upon these tests.

Initial Review of Abstracts. We will review all titles and abstracts identified through searches against our inclusion/exclusion criteria. Each abstract will be reviewed by at least 2 members of the investigative team. When differences between the reviewers arise, we will err on the side of inclusion. For studies without adequate information to make the determination, we will retrieve the full articles and review them against the inclusion/exclusion criteria.

C. Data Extraction and Data Management

Retrieve and Review Articles. We will retrieve and review all articles meeting our predetermined inclusion/exclusion criteria or for which we have insufficient information to make a determination. Each article will be reviewed by at least 2 members of the investigative team. When differences between the reviewers arise, we will err on the side of inclusion.

Determine Outcomes to Extract. We will set outcomes, including non-surgical harms, to extract a priori, determining critical outcomes related to pain management based on clinical expertise and our initial scan of the literature and abstract review. We have elected not to extract surgical harms as these data from selected pain intervention studies would not adequately capture all harms related to the surgical interventions.

Across the breadth of clinical presentations and clinical research in the realm of chronic pelvic pain there is not an established set of validated outcome measures. Therefore, we will not restrict this review to validated outcome measures. Rather, we will evaluate and describe selected outcome measures reported by individual studies and provide that data in a transparent way. For the quality assessment of an individual study, we will consider the established validity of the outcome measure(s) as one factor when assessing the outcome reporting bias.

The ideal outcome measure has the following attributes: (1) appropriateness of the measure’s content and conceptual model; (2) reliability; (3) validity; (4) responsiveness; (5) interpretability; (6) precision of scores; (7) respondent and administrator acceptability; (8) respondent and administrator burden and feasibility; (9) availability and equivalence of alternate forms and methods of administration (e.g. self-report, interviewer); and (10) availability and equivalence of versions for different cultures and languages.14

In evaluating the outcome measures the greatest weight is usually given to validity, reliability, responsiveness, appropriateness of content, and participant burden.14 Reliability, validity, and responsiveness can be condition or context specific and are not invariant properties of a measure.14

For the purpose of this review, we will consider outcome measures to be in two categories:

  1. Validated Outcome Measures:
    1. A Core Outcome Measure for chronic pain recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT)14
    2. An outcome measure described as validated by statements issued by an authoritative professional clinical organization (reference provided within the index study)
    3. An outcome measure described as validated by the authors of the index study, with a linked reference to the validation study, and appraisal of the validation study by 2 reviewers confirms validity established
  2. Other Outcome Measure
    1. An outcome measure described as validated by the authors of the index study, without a linked reference that provides authoritative statement from an independent professional clinical organization or a validation study, and not a Core Outcome Measure as described in 1a)
    2. An outcome measure that is not described as validated by the authors of the index study, and not a Core Outcome Measure as described in 1a

For the studies meeting the second-round assessment, the abstractors will extract key data and study quality elements from the article(s) and enter them into evidence tables. The Methods and Content Leads and content experts will review extraction forms against the original articles for quality control. Differences between the abstractor and the reviewer will be resolved by consensus.

We will develop a simple categorization scheme for coding the reasons that articles, at the stage of full review, are not finally included in the report. The abstractor will note the reason for exclusion on the article cover page. We will then record that code in an EndNote® database, our bibliography software, so that we can later compile a listing of excluded articles and the reasons for such exclusions.

Monitor Study Reviews. As reviews are conducted, the Project Coordinator and Administrative Support staff will track the status of each article. The Project Coordinator will maintain a master list of all the retrieved articles that indicates who was assigned the initial review and extraction, its status in the review and extraction process, the results of the review (e.g., whether it was selected for a full review or the reason why it was not, the date the initial review and extraction were completed, etc.).

The Project Coordinator will also monitor the progress of reviews. Weekly during the review phase of the study, the Project Coordinator will report the number of abstracts and articles out for review to the Methods and Content Leads, contact reviewers to determine progress and collect completed reviews, and assess each evidence table entries for completeness. Twice a month, the project staff will meet to discuss the results and progress to date; review cases that have been particularly difficult to classify, abstract, interpret or adjudicate; and address any questions the review team may have. In addition, all abstractors and other project team members will routinely use email to communicate any concerns or questions arising during the course of the reviews.

A study characteristics spreadsheet will be developed by the Project Coordinator and Administrative Support staff to aid the Content Lead, Content Experts, and Investigators in compiling abstracted data. These spreadsheets will allow each author to count key data points, such as study location, study type, and number of study participants.

D. Assessment of Methodological Quality of Individual Studies

Assess Study Quality. Quality assessment of individual studies will be performed using specific assessment tools for the type of study. For randomized controlled trials, the fundamental domains will include: adequate sequence generation, allocation concealment, blinding, incomplete outcome data addressed, and free of selective reporting bias.

For observational studies we will assess three broad perspectives: (1) the selection of the study groups; (2) the comparability of the groups; and (3) the ascertainment of either the exposure or outcome of interest for case-control or cohort studies respectively. For example, for a cohort study, the fundamental criteria will include: representativeness of cohort, selection of nonexposed cohort, ascertainment of exposure, outcome of interest, comparability of cohorts, assessment of outcome, adequate duration of follow-up, and adequate follow-up of cohort. Other sources of bias would include baseline imbalances, source of funding, early stopping for benefit, and appropriateness of crossover design.

Decision rules regarding detailed use of the quality assessment tools will be specified a priori by the review team. Two senior staff will independently perform quality assessment of the included studies with disagreements resolved through discussion or third party adjudication, as needed. We will record quality assessments in tables, summarizing for each study.

E. Data Synthesis

Prepare Evidence Tables. We will enter data into evidence tables, using predetermined abbreviations and acronyms and otherwise attending to consistency across entries from the outset. The dimensions (i.e., areas of special focus, or the columns) of each evidence table may vary by key question as appropriate, but the tables will contain some common elements, such as author, year of publication, study location (e.g., country, city, state) and time period, population description, sample size, and study type (e.g., randomized controlled trial, prospective observational study, etc).

F. Grading the Evidence for Each Key Question

Assess the Strength of Evidence. We will also utilize explicit criteria for rating the overall strength of the collective evidence on each key question into qualitative categories (e.g., low, moderate, high, insufficient). We will use established concepts of the quantity of evidence (e.g., numbers of studies, aggregate ending sample sizes), the quality of evidence (from the quality ratings on individual articles), and the coherence or consistency of findings across similar and dissimilar studies and in comparison to known or theoretically sound ideas of clinical or behavioral knowledge. We will make these judgments for each of the main key questions and any subquestions related to specific outcomes, as appropriate.

The strength of evidence evaluation will be that stipulated in the EHC Methods guidance, which emphasizes the following four major domains: risk of bias (low, medium, high), consistency (inconsistency not present, inconsistency present, unknown or not applicable), directness (direct, indirect), and precision (precise, imprecise). Risk of bias is derived from the quality assessment of the individual studies which addressed that Key Question and specific outcome under consideration. Each key outcome on each comparison of interest will be given an overall evidence grade based on the ratings for the individual domains.

The overall strength of evidence will be graded as “high” (indicating high confidence that the evidence reflects the true effect and further research is very unlikely to change our confidence in the estimate of effect); “moderate” (indicating moderate confidence that the evidence reflects the true effect and further research may change our confidence in the estimate of effect and may change the estimate); “low” (indicating low confidence that the evidence reflects the true effect and further research is likely to change our confidence in the estimate of effect and is likely to change the estimate); or “insufficient” (indicating that evidence is either unavailable or does not permit estimation of an effect). When no studies are available for an outcome or comparison of interest, the evidence will be graded as insufficient.

Two senior staff will independently grade the body of evidence, with disagreements resolved through discussion or third party adjudication, as needed. We will record strength of evidence assessments in tables, summarizing for each outcome.

References

  1. Williams RE, Hartmann KE, Steege JF. Documenting the current definitions of chronic pelvic pain: implications for research. Obstet Gynecol. Apr 2004;103(4):686-691.
  2. ACOG Practice Bulletin No. 51. Chronic pelvic pain. Obstet Gynecol. Mar 2004;103(3):589-605.
  3. Howard FM. Chronic pelvic pain. Obstet Gynecol. Mar 2003;101(3):594-611.
  4. Zondervan KT, Yudkin PL, Vessey MP, Dawes MG, Barlow DH, Kennedy SH. Patterns of diagnosis and referral in women consulting for chronic pelvic pain in UK primary care. Br J Obstet Gynaecol. Nov 1999;106(11):1156-1161.
  5. Howard FM. Treatment of chronic pelvic pain in women. UpToDate review. January 2010 2010(18.1).
  6. Howard FM. Evaluation of chronic pelvic pain in women. UpToDate review. January 2010 2010(18.1).
  7. Latthe P, Latthe M, Say L, Gulmezoglu M, Khan KS. WHO systematic review of prevalence of chronic pelvic pain: a neglected reproductive health morbidity. BMC Public Health. 2006;6:177.
  8. Mathias SD, Kuppermann M, Liberman RF, Lipschutz RC, Steege JF. Chronic pelvic pain: prevalence, health-related quality of life, and economic correlates. Obstet Gynecol. Mar 1996;87(3):321-327.
  9. Sepulcri Rde P, do Amaral VF. Depressive symptoms, anxiety, and quality of life in women with pelvic endometriosis. Eur J Obstet Gynecol Reprod Biol. Jan 2009;142(1):53-56.
  10. Stones RW, Mountfield J. Interventions for treating chronic pelvic pain in women. Cochrane Database Syst Rev. 2000(2):CD000387.
  11. Ortiz DD. Chronic pelvic pain in women. Am Fam Physician. Jun 1 2008;77(11):1535-1542.
  12. Purves AM PK, Munro C Defining chronic pain for epidemiological research—assessing a subjective definition. The Pain Clinic. 1998;10:139-147.
  13. International Association for the Study of Pain. Classification of chronic pain. Pain. 1986;Suppl 3:S1-S226.
  14. Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain. Jan 2005;113(1-2):9-19.

Definition of Terms – if applicable

For the purposes of this review, we will define chronic pelvic pain as pain of more than three months duration, localized to the anatomic pelvis (lower abdomen below umbilicus) of sufficient severity to cause functional disability or cause the patient to seek medical care; this three month timeframe is in alignment with published definitions of chronic pain,12-13 including that of the International Association for the Study of Pain, which defines chronic pain as “current continuous or intermittent pain or discomfort which has persisted for more than three months, with recent or frequent seeking of treatment or use of analgesic medication.”13

Summary of Protocol Amendments

Table 2. Summary of protocol amendments

Date

Section

Protocol Deviation

Rationale

November 15, 2010

Methods / Table 1

Clarification of approach to studies with participants with unclear pain status—for those studies that do not report data for women with cyclic and noncyclic pelvic pain separately, we will require that the study population include at least 80 percent of participants with noncyclic pain.

Many studies of CPP do not clearly differentiate between women with cyclic chronic pelvic pain (e.g., dysmenorrhea) and noncyclic pain in reporting baseline measures and outcomes. Studies may report the number of women with noncyclic pain at baseline, but follow-up results combine data for women with cyclic and noncyclic pain. Because the current review is focused on noncyclic pain, we will retain those studies whose populations are composed of at least 80 percent of women with noncyclic pain. We will note in our discussion of these studies that the results apply to the whole population and should be considered in that light.

November 15, 2010

Methods / Table 1

Clarification of approach to studies with participants who are less than 18 years of age—-for those studies that include subjects who are younger than 18 years but do not report data separately for women older than 18 years, we will require that the study population include at least 80 percent of participants older than 18 years.

Our review protocol limits the study population to women over the age of 18 years. Some studies (~9) include subjects who are younger than 18 years of age. There is empirical evidence that chronic noncyclic abdominal and pelvic pain in teenagers may have a different etiologic profile than noncyclic CPP in adults.  If a study does not specify the percentage of the study population who are younger than 18 years, we will attempt to calculate the likely percent and range, by interpolating from the mean age and age range data and other data provided.  We will note in our discussion of these studies that the results apply to the whole study population and should be considered in that light.

 

 

 

Table 2. Summary of protocol amendments (continued)

Date

Section

Protocol Deviation

Rationale

December 8, 2010

Methods / Table 1

Clarification of approach to studies including male participants—-for those studies that include both male and female participants, we will require that the study population include at least 80 percent female participants.

Our review protocol limits the study population to women over the age of 18 years. Some studies (~2) include male participants.  If a study population is composed of at least 80 percent women, we will retain the study and extract data on female participants only, where possible.  When extracting data on female subjects only is not possible, we will note in our discussion of these studies that the results apply to the whole study population and should be considered in that light.

February 4, 2011 Title Alignment of title and scope of review. We have focused this CER on women with noncyclic (i.e., not tied to any temporal associations) CPP based on input from our key informants and technical experts. To ensure that title of the review accurately matches its focus, we will change the CER title to “Comparative Effectiveness of Therapies for Women With Noncyclic Chronic Pelvic Pain.”

In the event of protocol amendments, the date of each amendment will be accompanied by a description of the change and the rationale.

NOTE: The following protocol elements are standard procedures for all protocols.

  1. Review of Key Questions
    For Comparative Effectiveness reviews (CERs) the key questions were posted for public comment and finalized after review of the comments. For other systematic reviews, key questions submitted by partners are reviewed and refined as needed by the EPC and the Technical Expert Panel (TEP) to assure that the questions are specific and explicit about what information is being reviewed.
  2. Technical Expert Panel (TEP)
    A TEP panel is selected to provide broad expertise and perspectives specific to the topic under development. Divergent and conflicted opinions are common and perceived as health scientific discourse that results in a thoughtful, relevant systematic review. Therefore study questions, design and/or methodological approaches do not necessarily represent the views of individual technical and content experts. The TEP provides information to the EPC to identify literature search strategies, review the draft report and recommend approaches to specific issues as requested by the EPC. The TEP does not do analysis of any kind nor contribute to the writing of the report.
  3. Peer Review (Standard Language)
    Approximately five experts in the field will be asked to peer review the draft report and provide comments. The peer reviewer may represent stakeholder groups such as professional or advocacy organizations with knowledge of the topic. On some specific reports such as reports requested by the Office of Medical Applications of Research, National Institutes of Health there may be other rules that apply regarding participation in the peer review process. Peer review comments on the preliminary draft of the report are considered by the EPC in preparation of the final draft of the report. The synthesis of the scientific literature presented in the final report does not necessarily represent the views of individual reviewers. The dispositions of the peer review comments are documented and will, for CERs and Technical briefs, be published three months after the publication of the Evidence report.

    It is our policy not to release the names of the Peer reviewers or TEP panel members until the report is published so that they can maintain their objectivity during the review process.
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