Noncyclic Chronic Pelvic Pain Therapies for Women

1. Noncyclic Chronic Pelvic Pain Therapies for Women Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov

2. Outline of Material • Introduction to noncyclic chronic pelvic pain (CPP) and available surgical and non-surgical treatment options • Systematic review methods • The clinical questions addressed by the CER • Results of studies and evidence-based conclusions about the relative effectiveness of various therapies for noncyclic CPP • Gaps in knowledge and future research needs • What to discuss with patients and their caregivers Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm.

3. Background: Definition of Noncyclic CPP and Its Prevalence • For the purpose of this review, noncyclic CPP was defined as pain that: • Has persisted for more than 3 months • Is localized to the anatomic pelvis • Causes the patient to become functionally disabled or seek medical care • Always has a noncyclic component, and may have mixed cyclic and noncyclic components • Is not limited to dysmenorrhea, dyspareunia, dyschezia, or dysuria • This review focused on women over the age of 18 with CPP. • Prevalence estimates of noncyclic CPP vary and range from 4.0 to 43.4%. Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm. Latthe P, Latthe M, Say L, et al. BMC Public Health 2006;6:177. PMID: 16824213.

4. Background: Etiology of Noncyclic CPP • Gynecological causes for noncyclic CPP include: • Endometriosis • Pelvic inflammatory disease • Adhesions • Pelvic floor muscle spasm • Nongynecological causes of CPP include: • Irritable bowel syndrome (IBS) • Interstitial cystitis (IC)/painful bladder syndrome (PBS) • Myofascial pain disorders • Depression • In some cases, a definite underlying cause for CPP may not be identified. Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at ww.effectivehealthcare.ahrq.gov/pelvicpain.cfm. Ortiz DD. Am Fam Physician 2008;77:1535-42. PMID:18581833.

5. Background: Burden of Noncyclic CPP • Noncyclic CPP can have significant impact on a woman’s • Physical functioning • Psychological well-being • Social functioning • Quality of life • A study conducted in the United States estimated that: • $880 million were spent annually on outpatient management of CPP. • 15% of women with CPP reported time lost from work. Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm. Ortiz DD. Am Fam Physician.2008;77:1535-42. PMID: 18581833. Mathias SD, Kupperman M, Liberman RF, et al. Obstet Gynecol. 1996;87:321. PMID: 8598948

6. Background: Comorbidities Associated With Noncyclic CPP • Comorbidities and factors associated with noncyclic CPP include: • IBS • IC/PBS • Endometriosis • Psychological comorbidities (depression, anxiety, sleep disorders) • General factors (history of physical or sexual abuse) • Obstetric factors (history of miscarriage or cesarean birth) • Diagnosis and reporting of comorbidities in CPP is complex since: • Uniform definitions and diagnostic criteria for comorbidities are lacking. • One or more conditions can co-occur with CPP or cause CPP. Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm. Zondervan KT, Yudkin PL, Vessey MP, et al. Am J Obstet Gynecol 2001;184:1149-55. PMID: 11349181.

7. Background: Evaluation of Noncyclic CPP • Methods for evaluating and diagnosing noncyclic CPP include: • Patient evaluation including pain history, pain mapping to determine etiology, and initial therapeutic course • Diagnostic laparoscopy to identify and treat pathologies such as endometriosis and adhesions that cause CPP • Assessment of physical, psychological, and social factors associated with CPP for comprehensive management of the condition Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm. Ortiz DD. Am Fam Physician 2008;77:1535-42. PMID: 18581833.

8. Background: Uncertainties Associated With Therapies for Noncyclic CPP • For patients in whom the etiology of CPP is unknown or unclear, the condition is often managed based on clinician experience; a standard treatment algorithm is lacking. • The benefits and harms of the available therapeutic modalities have not been thoroughly investigated. • When an initial treatment approach fails, the rationale for selecting one intervention over another lacks guidance from evidence. Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm.

9. Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development • Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others. •  A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment. •  The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The Summaries and the full reports, with references for included and excluded studies, are available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm.

10. Clinical Questions Addressed by the CER (1 of 2) • Key Question (KQ) 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, IBS, IC/PBS, complex regional pain syndrome, vulvodynia, functional abdominal pain syndrome, low back pain, headache, and sexual dysfunction? • KQ 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? Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No.41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm.

11. Clinical Questions Addressed by the CER (2 of 2) • Key Question (KQ) 3: What is the evidence that surgical outcomes differ if the etiology of noncyclic/mixed cyclic and noncyclic CPP is identified after surgery? • KQ 4: Among women with noncyclic/mixed cyclic and noncyclic CPP, what is the effect of non-surgical interventions on pain status, functional status, satisfaction with care, quality of life, and harms? • KQ 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)? Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm.

12. Rating the Strength of Evidence From the CER • The strength of evidence was classified into four broad categories: Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm.

13. Prevalence of Comorbidities in Women With Noncyclic CPP • Prevalence estimates for the most common comorbidities occurring in patients with CPP were: • Dyspareunia — 15–88% • Dysmenorrhea — 4–100% • IBS — 24–39% • Prevalence estimates for comorbidities varied widely due to lack of standardized definitions and complexity of their diagnosis. • Strength of evidence was not assessed for this Key Question since it did not focus on interventions. Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm.

14. Therapeutic Interventions for CPPAssessed in the CER • Non-surgical interventions • Pharmacologic interventions • Antineuropathics (gabapentin, amitriptyline) • Neuromuscular blocking agents (botulinum toxin A) • Hormonal interventions • Estrogen/progesterone contraceptive agents (in oral, transdermal, or injection form) • Gonadotropin releasing hormone analogs (depot leuprolide, goserelin, gestrinone) • Selective estrogen receptor modulator (raloxifene) • Other interventions • Physical therapy (pelvic ultrasonography, pelvic floor muscle exercises) • Counseling with or without photographic reinforcement* • Integrated treatment approach† • Surgical interventions • Laparoscopic uterine nerve ablation (LUNA) • Laparoscopic adhesiolysis • Uterosacral ligament resection * Photographic enforcement = displaying operative photographs † Integrated treatment approach = equal attention devoted to organic, psychological, dietary, and environmental causes of pain; laparoscopy not routinely performed. Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm.

15. Comparative Effectiveness of Non-surgical Interventions for Noncyclic CPP: Pain Outcomes (1 of 2) • Evidence from one RCT suggested that there was an earlier return to pain with raloxifene than with placebo. Strength of evidence: low • Evidence from one RCT suggested that there was greater reduction in pain with depot leuprolide when compared with placebo. Strength of evidence: low Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm.

16. Comparative Effectiveness of Non-surgical Interventions for Noncyclic CPP: Pain Outcomes (2 of 2) • Evidence was insufficient to permit meaningful conclusions about the relative effectiveness of the following interventions in improving pain status: • Hormonal therapies except raloxifene or depot leuprolide versus placebo • Gabapentin + amitriptyline versus amitriptyline alone • Botulinum toxin versus placebo • Pelvic ultrasonography plus counseling versus expectant management • Pelvic floor muscle therapy versus counseling • Photographic reinforcement versus no reinforcement during post-operative counseling • Integrated treatment approach† versus standard treatment†† Strength of evidence: insufficient † Integrated treatment approach = equal attention devoted to organic, psychological, dietary, and environmental causes of pain; laparoscopy not routinely performed. †† Standard treatment = exclusion of organic causes of pain and routine laparoscopy before attention is devoted to treating other causes. Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm.

17. Comparative Effectiveness of Surgical Interventions for Noncyclic CPP: Pain and Quality-of-Life Outcomes (1 of 2) • There was no significant difference between laparoscopic uterine nerve ablation (LUNA) and diagnostic laparoscopy for improving pain status in CPP patients. • Evidence was based on 2 RCTs, including one with 5 years followup, in patients with endometriosis, adhesions or pelvic inflammatory disease. Strength of evidence: low • Laparoscopic adhesiolysis and diagnostic laparoscopy were similarly effective in improving pain scores and quality of life. • Evidence was based on 1 RCT in patients with CPP associated with adhesions who were followed up for 12 months. Strength of evidence: low Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm.

18. Comparative Effectiveness of Surgical Interventions for Noncyclic CPP: Pain and Quality-of-Life Outcomes (2 of 2) • Evidence was insufficient to permit meaningful conclusions about the relative effectiveness of the following interventions in improving pain status: • LUNA versus uterosacral ligament resection • Surgical versus non-surgical therapy Strength of evidence: insufficient Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm.

19. Comparative Effectiveness of Surgical Interventions for Noncyclic CPP: Functional Outcomes • Evidence was insufficient to permit meaningful conclusions about the relative effectiveness of hysterectomy versus non-surgical therapy in improving functional status. Strength of evidence: insufficient Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm.

20. Conclusions (1 of 2) • A thorough work-up may be required in patients with CPP given the various possible etiologies for this condition. • In patients with CPP where endometriosis is suspected, there may be benefit to hormonal therapy. • Among surgical approaches for CPP, both LUNA and laparoscopic adhesiolysis were not found to be superior to diagnostic laparoscopy. • Examination of current evidence is insufficient to change current approaches to care. • Use of less-invasive therapeutic interventions may be warranted before moving on to more invasive approaches, which could be associated with increased harms. Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm.

21. Conclusions (2 of 2) • The limited evidence suggests that current standard treatment practices are not well supported by existing research. • Improved characterization of the condition, intervention, and population in CPP research is necessary to inform treatment choices for this commonly reported entity. • There is an urgent need to address gaps in knowledge regarding decisionmaking for this condition. Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm.

22. Knowledge Gaps and Future Research Needs (1 of 2) • There are very few data on outcome measures such as quality of life, functional status, and patient satisfaction in studies of noncyclic CPP. • The evidence on hormonal therapies for noncyclic CPP that is not associated with endometriosis is limited. • There is a paucity of noncyclic CPP studies evaluating nonhormonal and nonpharmacological interventions, and comparing medical and surgical management. Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm.

23. Knowledge Gaps and Future Research Needs (2 of 2) • Prevalence estimates of noncyclic CPP-associated comorbidities (such as dyspareunia, dysmenorrhea, IBS, and major depressive disorder) are widely variable. • There is limited understanding of the role of a multidisciplinary approach in managing noncyclic CPP despite its complex, multifactorial etiology. Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm.

24. What To Discuss With Your Patientsand Their Caregivers • The uncertainty about noncyclic CPP therapies • The different types of interventions available for treating noncyclic CPP • The types of comorbidities and factors (including psychosocial) that might be associated with noncyclic CPP and the importance of these in deciding treatment • The possibility that a definitive cause of the patient’s noncyclic CPP may not be identified, making the treatment process complex • Encouraging the patient to work with you to identify an optimal approach to manage the condition Andrews J, Yunker A, Reynolds WS, et al. Comparative Effectiveness Review No. 41. Available at www.effectivehealthcare.ahrq.gov/pelvicpain.cfm.