{"paper_id":"495c4b56-96d9-464b-9373-998ff1314e42","body_text":"CHRONIC PELVIC PAIN: PREVALENCE, RISK \nFACTORS AND LAPAROSCOPIC UTEROSACRAL \nNERVE ABLATION \n \nPALLAVI LATTHE \nA thesis submitted to the Faculty of Medicine and Dentistry of the University of \nBirmingham for the degree of \nDOCTOR OF MEDICINE \n \nAcademic Department of Obstetrics and Gynaecology \nFaculty of Medicine and Dentistry \nThe University of Birmingham \nAugust 2005 \n\n \n \n \n \n \n \n \n \n \nUniversity of Birmingham Research Archive \n \ne-theses repository \n \n \nThis unpublished thesis/dissertation is copyright of the author and/or third \nparties. The intellectual property rights of the author or third parties in respect \nof this work are as defined by The Copyright Designs and Patents Act 1988 or \nas modified by any successor legislation.   \n \nAny use made of information contained in this thesis/dissertation must be in \naccordance with that legislation and must be properly acknowledged.  Further \ndistribution or reproduction in any format is prohibited without the permission \nof the copyright holder.  \n \n \n \n\nSYNOPSIS \nThis thesis sheds light on chronic pelvic pain in following areas: 1. Summarising prevalence \nof chronic pelvic pain 2. Exploring the risk fact ors in chronic pelvic pain, 3. Exploring beliefs \non laparoscopic uterosacral nerve ablation and 4. Developing a protocol for a Multicentre \nrandomised controlled trial of laparoscopic uterosacral nerve ablation.  \n i\n\nEXECUTIVE ABSTRACT \nObjective \nThis thesis has the following objectives:  \n1. To estimate the prevalence of chronic pelvic  pain (CPP) by means of a systematic \nreview \n2. To generate pooled evidence on the aetiology of CPP by means of systematic review \n3. To undertake a questionnaire survey of practice concerni ng laparoscopic uterosacral \nnerve ablation (LUNA) in Europe \n4. To undertake a questionnaire survey of beliefs concerning effectiveness of LUNA  \n5. To determine the effectiveness of neuroabl ation in CPP by means of a systematic \nreview  \n6. To develop a protocol for a prospective ra ndomised controlled trial (RCT) to assess \nthe effectiveness of LUNA in CPP \nMethods \nThe work undertaken in this thesis was based on prospective study protocols using the \nfollowing research methodologies: \n• Systematic reviews and meta-analyses to meet objectives 1, 2 and 5 \n• Structured questionnaires to meet objectives 3 & 4  \n• RCT to meet objective 6 \n ii\n\nResults \n1. There was significant variation among rates of all three types of CPP. Metaregression \nanalysis showed that this heterogeneity was mainly due to non-representativeness of \nstudy sample and inadequacy of study methods. Meta-analysis of rates amongst high \nquality studies with samples representative of general population showed that \nprevalence of dysmenorrhoea (12 studies) was 59% (95% CI 49.1-71%, heterogeneity \np<0.001), of dyspareunia (11 studies) was 13.3% (95% CI 8.8-20.3%, heterogeneity \np<0.001) and of noncyclical pain (2 studies) was 6.2% (95% confidence interval (CI) \n3-12.6%, heterogeneity p <0.001).  \n2. Age less than 30 years, low body mass index (BMI), smoking, early menarche (<11 \nyears), longer cycles, longer duration of bleeding or heavy menstrual flow, nulliparity, \npremenstrual syndrome, sterilisation, pelvic inflammatory disease (PID), sexual \nassault, emotional difficulties, psychological symptoms, suicidal tendency and \nsomatisation were associated with increased risk of dysmenorrhoea. Younger age at \nfirst childbirth, exercise and oral contraceptives were associated with reduction in the \nrisk of dysmenorrhoea. Peri/post menopausal state, PID, sexual abuse, anxiety and \ndepression were found to be associated with dyspareunia. Drug/alcohol abuse, \nmiscarriage, heavier menstrual flow, PID, previous caesarean section, pelvic \nadhesions/other pathology, childhood physical or sexual abuse, lifetime sexual abuse, \nanxiety, depression, hysteria, psychosomatisation were associated with an increased \nrisk of noncyclical pelvic pain. \n3. Indications for LUNA, which included noncyc lical chronic pelvic pain (CPP) (68%), \ndysmenorrhoea (66%), dyspareunia (39%) or  endometriosis (60%), were similar \nacross UK and rest of Europe. The European group performed LUNA more often \n iii\n\n(62% vs. 21%), completely transected th e uterosacral ligaments (56% vs. 36%) and \nablated at a distance of more than 2 cm from its cervical insertion (50% vs. 21%) more \nfrequently than the UK group. More experienced gynaecologists performed LUNA \nmore for dyspareunia (46 % vs. 26%) and endometriosis (67% vs. 47%) and they \nperformed complete transection (45% vs.26%) more often than their less experienced \ncounterparts. \n4. The most widely held ‘prior’ belief, reflected in both questionnaire and numerical \nresponses was that LUNA would have a small beneficial effect on pain. The credible \nlimits of this belief were compatible with large reductions in pain as 60% of \nrespondents believed a three-point improvement on VAS to be plausible. \n5. For the treatment of primary dysmenorrhoea, laparoscopic uterosacral nerve ablation \n(LUNA) at 12 months was better when compared to a control or no treatment. The \ncomparison of LUNA with presacral neurectomy (PSN) for primary dysmenorrhoea \nshowed that at 12 months follow up, PSN was more effective. In secondary \ndysmenorrhoea, along with laparoscopic surgical treatment of endometriosis, the \naddition of LUNA did not improve the pain relief while PSN did. Adverse events were \nmore common for PSN. \n6. The LUNA trial protocol has been granted ethical approval. A total of 410 women \nhave been randomised (September 2004). Interim analyses by an independent data \nmonitoring committee have shown that the two groups are comparable in age, parity, \ntype of CPP and baseline pain scores. \nConclusion \n1. The variation in rates of CPP worldwide is explained by variable study quality. High \nquality literature revealed a high burden of disease. \n iv\n\n2. Key gynaecological and psychosocial factors associated with CPP should be targeted \nin clinical evaluation of women with this symptom to individualise their management. \n3. There is variation in the surgical techni ques of performing LUNA in Europe and the \ntechniques vary according to operator experience. \n4. Among gynaecologists, there is a variation in beliefs about the effects of LUNA on \npelvic pain, ranging from substantial benefit to slight harm. \n5. The evidence to recommend the use of nerv e interruption in the management of \ndysmenorrhoea, regardless of cause, is sti ll insufficient. Methodologically sound and \nsufficiently powered RCTs should be undertaken in future. \n6. The LUNA trial is the largest trial of neuroablation thus far. It is hoped that if the \nresults of the trial are positive, women suffering from this common and difficult to \ntreat condition will benefit from this simple operation. If the results are negative a \nreliable basis for discouraging the spread of this technique will have been provided. \n v\n\nDEDICATION \nI dedicate this thesis to my husband, Manish and my children, Anya and Varun for giving me \nthe time to pursue my research, my parent s-in-laws for their continuing support and \nencouragement and to my parents who enthused me through difficult times and taught me to \ncarry on relentlessly in the face of trying times. \n vi\n\nACKNOWLEDGEMENTS \n \nThis work was undertaken while I was a re search fellow co-ordinating Laparoscopic \nUterosacral nerve ablation (LUNA) trial and was based at Birmingham Women’s Hospital, \nUK, between September 2002 and September 2004. This trial was funded by WellBeing of \nWomen and WHO supported one of the systematic reviews. \n \nI am indebted to my research supervisor and fr iend, Khalid Khan, Professor of Obstetrics and \nGynaecology, Clinical Sub-Dean, for the expe rt guidance and continued support through the \nyears, and the many hours spent on the various research projects leading to this thesis. I would \nlike to thank my other supervis or, Professor Richard Gray, Dir ector of Birmingham Clinical \nTrials Unit, University of Birmingham for con tinued help and mentoring.  This work would \nnot have been possible withou t my co-workers especially Mr Janesh Gupta, Mr David \nBraunholtz, Jane Daniels, Dr. R obert Hills, Dr. Luci ano Mignini and Prof . Richard Lilford. I \nwould like to thank Mrs Mary Publicover and Mr Derek Yates of the Education Resource \nCentre for their assistance with the searches  and obtaining articles required for the work \npresented in this thesis. I would like to acknowledge the friendly advice and tips from my \nfriends Dr. Honest, Dr. Clarke and Dr. Arri Coomarsamy. Finally, I would emphasise that this \nwork would not be complete without my co-w orkers on various projects (Appendix 1.1), who \nmight or might not be mentioned in the appendix of contributions. \n vii\n\nTABLE OF CONTENTS \nSYNOPSIS................................................................................................................................. I \nEXECUTIVE ABSTRACT.....................................................................................................II \nOBJECTIVE...............................................................................................................................II \nMETHODS ................................................................................................................................II \nRESULTS.................................................................................................................................III \nCONCLUSION ..........................................................................................................................IV \nDEDICATION ....................................................................................................................... VI \nACKNOWLEDGEMENTS .................................................................................................VII \nTABLE OF CONTENTS .........................................................................................................1 \nLIST OF FIGURES..................................................................................................................4 \nLIST OF TABLES....................................................................................................................5 \nLIST OF ABBREVIATIONS..................................................................................................7 \nPUBLICATIONS FROM THIS THESIS ..............................................................................8 \nCHAPTER 1: INTRODUCTION .........................................................................................10 \n1.1 D EFINITION OF CHRONIC PELVIC PAIN........................................................................11 \n1.2 P REVALENCE OF CHRONIC PELVIC PAIN .....................................................................12 \n1.3 A ETIOLOGY OF CHRONIC PELVIC PAIN .......................................................................13 \n1.4 A NATOMY OF PAIN PATHWAY AND RATIONALE FOR NERVE ABLATION ......................14 \n1.5 S URVEY OF PRACTICE OF LUNA...............................................................................16 \n1.6 C LINICIANS’ BELIEFS ABOUT EFFECTIVENESS OF LUNA ...........................................17 \n1.7 R ESEARCH EVIDENCE ON EFFECTIVENESS OF LUNA.................................................18 \n1.8 A IMS AND OBJECTIVES...............................................................................................18 \nSECTION A: PREVALENCE AND AETIOLOGY OF CHRONIC PELVIC PAIN .....20 \nCHAPTER 2: WORLDWIDE PREVALENCE  OF CHRONIC PELVIC PAIN: A \nSYSTEMATIC REVIEW AND META-ANALYSES.........................................................21 \n2.1 ABSTRACT ...................................................................................................................22 \n 1\n\n2.2 INTRODUCTION..........................................................................................................24 \n2.3 METHODS .....................................................................................................................24 \n2.4 RESULTS .......................................................................................................................28 \n2.5 DISCUSSION.................................................................................................................37 \nCHAPTER 3: RISK FACTORS IN CHRO NIC PELVIC PAIN: A SYSTEMATIC \nREVIEW AND META-ANALYSES ....................................................................................40 \n3.1 ABSTRACT ...................................................................................................................41 \n3.2 INTRODUCTION..........................................................................................................43 \n3.3 METHODS .....................................................................................................................44 \n3.4 RESULTS .......................................................................................................................48 \n3.5 DISCUSSION.................................................................................................................55 \nSECTION B: SURVEY OF PRACTICE OF LAPAROSCOPIC UTEROSACRAL \nNERVE ABLATION..............................................................................................................59 \nCHAPTER 4: VARIATION IN PRACTICE  OF LAPAROSCOPIC UTEROSACRAL \nNERVE ABLATION: A EUROPEAN SURVEY................................................................60 \n4.1 ABSTRACT ...................................................................................................................61 \n4.2 INTRODUCTION ..........................................................................................................63 \n4.3 METHODS .....................................................................................................................64 \n4.4 RESULTS.......................................................................................................................65 \n4.5 DISCUSSION.................................................................................................................69 \nCHAPTER 5: MEASUREMENT OF ‘PRI OR’ BELIEFS ABOUT EFFECTIVENESS \nOF LAPAROSCOPIC UTEROSACRAL NERVE ABLATION.......................................72 \n5.1 ABSTRACT ...................................................................................................................73 \n5.2 INTRODUCTION..........................................................................................................74 \n5.3 METHODS.....................................................................................................................75 \n5.4 RESULTS.......................................................................................................................77 \n 2\n\n5.5 DISCUSSION.................................................................................................................81 \nSECTION C: EVIDENCE ON EFFECT IVENESS OF LUNA AND LUNA TRIAL \nPROTOCOL ...........................................................................................................................83 \nCHAPTER 6: EFFECTIVENESS OF NEUROABLATION IN RELIEVING CHRONIC \nPELVIC PAIN (DYSMENORRHOEA): UP DATE OF COCHRANE SYSTEMATIC \nREVIEW .................................................................................................................................84 \n6.1 ABSTRACT ...................................................................................................................85 \n6.2 INTRODUCTION..........................................................................................................87 \n6.3 METHODS.....................................................................................................................88 \n6.4 RESULTS.......................................................................................................................90 \n6.5 DISCUSSION.................................................................................................................98 \nCHAPTER 7: A RANDOMISED CONTRO LLED TRIAL TO ASSESS THE \nEFFECTIVENESS OF LAPAROSCOPIC  UTEROSACRAL NERVE ABLATION \n(LUNA) IN CHRONIC PELVIC PAIN: THE TRIAL PROTOCOL .............................101 \n7.1 ABSTRACT .................................................................................................................102 \n7.2 INTRODUCTION........................................................................................................104 \n7.3 METHODS...................................................................................................................105 \n7.4 RESULTS.....................................................................................................................116 \n7.5 DISCUSSION...............................................................................................................122 \nCHAPTER 8 SUMMARY ...................................................................................................127 \n8.1 SUMMARY OF FINDINGS .................................................................................................128 \n8.2 IMPLICATIONS FOR CLINICAL PRACTICE .........................................................................131 \n8.3 IMPLICATIONS FOR RESEARCH PRACTICE .......................................................................132 \nTABLE OF CONTENTS OF APPENDICES....................................................................134 \nLIST OF REFERENCES.....................................................................................................136 \n 3\n\nLIST OF FIGURES \nChapter 1 \n1.1 Pelvic nerve pathway \n \n25 \nChapter 2 \n2.1 Study selection process for systematic review of prevalence of chronic \npelvic pain \n \n \n37 \n2.2 Quality of the included studies 38 \n2.3 Prevalence rates of different types of chronic pelvic pain amongst included \nstudies \n39 \n \n2.4 Data synthesis of studies on prevalence of different types of chronic pelvic \npain.  \n40 \n2.5 Epimaps of worldwide prevalence of different types of chronic pelvic pain 42 \n2.6 Funnel plots of the three types of pelvic pain prevalence studies 43 \nChapter 3 \n3.1 Study selection process for systematic review of risk factors in chronic \npelvic pain \n \n55 \n3.2 Methodological quality of studies included in the systematic review 56 \n3.3 Meta-analysis of the risk factors associated with dysmenorrhoea 57 \n3.4 Meta-analysis of the risk factors associated with dyspareunia 58 \n3.5 Meta-analysis of the risk factors associated with noncyclical pelvic pain 60 \nChapter 5 \n5.1 A sample of a graphical elicitation of beliefs about the likely true effect of \nlaparoscopic uterosacral nerve ablation (LUNA) compared to placebo \n \n81 \n5.2 Graphical representation of ‘prior’ beliefs about effectiveness of \nlaparoscopic uterosacral nerve ablation \n84 \n5.3 Agreement between graphical and textual representation of beliefs of \neffects of laparoscopic uterosacral nerve ablation (LUNA)  \n86 \nChapter 6 \n6.1 Study selection process for systematic review of neuroablation in \ndysmenorrhoea \n97 \n6.2 Methodological quality of studies included in the systematic review of \neffectiveness of neuroablation in dysmenorrhoea \n \n98 \n6.3 Results of metanalyses of effectiveness of neuroablation in dysmenorrhoea 102 \nChapter 7 \n7.1 The LUNA trial schema 111 \n 4\n\nLIST OF TABLES \nChapter 1 \n1.1 Structured questions for each chapter of this thesis \n \n24 \nChapter 2 \n2.3 Table of characteristics of studies included in systematic review on \nthe worldwide prevalence of dysmenorrhoea \nCD ROM \n26 \n2.4 Table of characteristics of studies included in systematic review on \nthe worldwide prevalence of dyspareunia \nCD ROM \n71 \n2.5 Table of characteristics of studies included in systematic review on \nthe worldwide prevalence of noncyclical pelvic pain \nCD ROM \n89 \n2.6 Metaregression to explore heterogeneity in the systematic review on \nprevalence of chronic pelvic pain \nCD ROM \n96 \n2.7 Compliance of systematic review on the worldwide prevalence of \nchronic pelvic pain with The MOOSE Checklist \n \nCD ROM \n98 \nChapter 3 \n3.5 Table of characteristics of included studies on dysmenorrhoea CD ROM \n124 \n3.6 Table of quality assessment of included studies on dysmenorrhoea CD ROM \n162 \n3.7 Table of results of included studies on dysmenorrhoea CD ROM \n173 \n3.8 Table of characteristics of included studies on dyspareunia CD ROM \n199 \n3.9 Table of quality assessment of included studies on dyspareunia CD ROM \n205 \n3.10 Table of results of included studies on dyspareunia CD ROM \n210 \n3.11 Table of characteristics of included studies on noncyclical chronic \npelvic pain \nCD ROM \n213 \n3.12 Table of quality assessment of included studies on noncyclical \nchronic pelvic pain \nCD ROM \n228 \n3.13 Table of results of included studies on noncyclical chronic pelvic pain CD ROM \n238 \n3.14 Table of Compliance of ‘Factors predisposing women to chronic \npelvic pain: A Systematic Review’ with The MOOSE Checklist  \n \nCD ROM \n258 \nChapter 4 \n4.1 Responses to the questionnaires on practice of Laparoscopic \nUterosacral Nerve Ablation (LUNA) in the UK and the rest of Europe \n71 \n4.2 Comparison of indications for laparoscopic uterosacral nerve ablation \n(LUNA) \n72 \n4.3 Laparoscopic uterosacral nerve ablation (LUNA) techniques, \nmanagement of minimal-mild endometriosis and comparison of \ntechniques by experience \n73 \n 5\n\n \nChapter 5 \n5.1 Clinicians’ textual ‘priors’ beliefs on the effect of laparoscopic \nuterosacral nerve ablation (LUNA) on pain \n \n83 \n \nChapter 6 \n6.1 Table of characteristics of studies included in the systematic review on \neffectiveness of neuroablation in dysmenorrhoea \n \nCD ROM \n273 \n6.3 Table of compliance of the neuroablation in dysmenorrhoea: \nsystematic review of effectiveness with the QUOROM checklist \nCD ROM \n284 \nChapter 7 \n7.1 Study Flow Chart 110 \n7.2 Baseline characteristics of participants in the LUNA trial 115-116 \n7.3 Baseline VAS scores of pain, EUROQoL scores and sexual \nsatisfaction scores of participants in the LUNA trial \n117 \nChapter 8 \n8.1 Structured answers for each chapter of the thesis \n \n133-135 \n \n 6\n\n \nLIST OF ABBREVIATIONS \nAFS American fertility score \nBISS Brief Index of sexual satisfaction \nBCTU Birmingham university clinical trials unit \nCPP Chronic pelvic pain \nGP General practitioner \n5D EQ 5 dimensional European quality of life questionnaire \nITT Intention to treat \nLUNA Laparoscopic uterosacral nerve ablation \nCI Confidence intervals \nO&G Obstetrics and Gynaecology \nOCP Oral contraceptive pills \nOR Odds ratio \nPID Pelvic inflammatory disease \nRCT Randomised controlled trial \nRev Man Review Manager 4.2 \nSAQ Sexual activity questionnaire \nSR Systematic review \nUK United Kingdom \nVAS Visual analogue scale \n \n 7\n\nPUBLICATIONS FROM THIS THESIS \n• Latthe PM, Khan KS for the LUNA Trial Steering Group: A randomised controlled \ntrial to assess the efficacy of Laparoscopic Uterosacral Nerve Ablation (LUNA) in the \ntreatment of chronic pelvic pain: The trial protocol [ISRCTN41196151]. BMC \nWomens Health. 2003 Dec 08; 3 (1): 6. \n• Latthe PM, Powell RJ, Hills RK, Gupta JK, Gray R, Khan KS. Variation in practice \nof Laparoscopic uterosacral nerve ablation: A European survey. Journal of Obstetrics \nand Gynaecology; 2004 Aug; 24(5): 547-51 \n• Latthe PM, Khan KS. Commentary in Evidence Based O &G on the recent trials in \nneuroablation for pelvic pain; 2003; 11: 6-16 \n• Latthe PM, Braunholtz D, Hills RK, Khan KS, Lilford RJ. Measurement of beliefs \nabout effectiveness of laparoscopic uterosacral nerve ablation BJOG An International \nJournal of Obstetrics and Gynaecology;\n 2005 Feb; 112(2): 243-6.  \n• Proctor M, Latthe PM, Prof. Farquhar C.M, Johnson N, Prof. Khan KS. Surgical \ninterruption of pelvic nerve pathways in dysmenorrhea: A systematic review of \neffectiveness (Cochrane library August 2005) \n• Latthe PM, Proctor M, Prof. Farquhar C.M, Johnson N, Prof. Khan KS. Surgical \ninterruption of pelvic nerve pathways in dysmenorrhea: A systematic review of \neffectiveness (Accepted for publication in Acta Obstetriticia et Gynecologica \nScandinavica)  \n• Latthe PM, Mignini LM, Gray R, Khan KS. Factors predisposing women to chronic \npelvic pain: A Systematic Review (Accepted for publication in BMJ) \n \n\n  \nArticles submitted for publication: \n• Latthe PM, Latthe M, Say L, Gulmezoglu M, Khan KS. Worldwide prevalence of \nchronic pelvic pain: A systematic review and meta-analysis of a neglected health \nproblem (BMC Public Health) \n 9\n\n \nCHAPTER 1: INTRODUCTION \n 10\n\n  \n1.1 Definition of chronic pelvic pain \nThere are many definitions for chronic pelvic pain (CPP). An existing systematic review \nobserved that definitions for CPP vary greatly in the published literature.1 The definitions may \nconsider duration of pain, location and type of pain and relationship to menstruation and \nsexual activity. One definition is ‘recurrent or constant pain in the lower abdominal region \nthat has lasted for at least 6 months’. 2 Another definition is: ‘nonmen strual pain of 3 or more \nmonths duration that localizes to the anatomic pelvis and is severe enough to cause functional \ndisability and require medica l or surgical treatment’. 3 Although the choice of 3- 6 months’ \nduration within a definition is ar bitrary, it does not carry the subjective anatomic or affective-\nbehavioural assumptions that other types of definitions have used. 4  \n \nThe International Association for the study of Pain have provided a specific definition for \n‘CPP without obvious pathology’: ch ronic or recurrent pelvic pain  that cannot be  sufficiently \nexplained by an apparent physical cause; 5 this is sometimes also called as the ‘pelvic pain \nsyndrome’6 or ‘pelvalgia’. 7 This definition of CPP does not specifically include pain \nassociated with the menses or sexual inte rcourse. A common definition, including these \nissues, is: constant or intermittent, cyclic or nonc yclic pain that persists for 6 months or more \nand includes dysmenorrhoea, deep dyspareunia and intermenstrual pain’.8 This definition will \nbe used for CPP in this thesis. \n \nDysmenorrhoea is the occurrence of pain ful menstrual cramps of uterine origin. \nDysmenorrhoea is a very common gynaecological complaint that can affect up to 50% of \nwomen,9 and as such has a signif icant impact not just on personal health but also \neconomically, through lost working hours. 10 Dysmenorrhoea is commonly defined in two \n 11\n\n \nsubcategories. When the menstrual pelvic pain is associated with an identifiable pathological \ncondition, such as endometriosis, adenomyosis  or pelvic adhesions  reflecting previous \ninflammation, it is considered to  be secondary dysmenorrhoea. In contrast, menstrual pain \nwithout organic pathology is consid ered to be primary dysmenorrhoea. 11 According to \nstandard gynaecological texts, primary dysmenorrho ea usually occurs at or shortly after (6 to \n12 months) menarche, when ovulatory cycles are established. The pain duration is typically \n48 to 72 hours and is associated  with menstrual flow. In cont rast secondary dysmenorrhoea is \nmore likely to occur years after the onset of menarche and occur premenstrually as well as \nduring menstruation. In practice, the accuracy of diagnosis depends on the availability and the \nuse of diagnostic tools. \n \n1.2 Prevalence of chronic pelvic pain  \nThe prevalence rate of a condition in a populati on is the proportion of the population that has \nthe condition at a specific point  in time (point prevalence) or at some point in a time period \n(period prevalence). Prevalence rates for CPP w ill be difficult to ascertain in light of the \nvarying definitions used in the literature as  highlighted above. In a recent UK study, women \naged between 12-70 years had an annual prevalence of 38/1000 of CPP defined as recurrent or \nconstant pain in the area from navel down in the lower belly of at least 6 months duration, \nunrelated to periods, intercourse or pregnancy. This compares to  the rate of asthma (37/1000) \nand chronic back pain (41/1000) in the community. 12  \n \nPrevalence rates for dyspareunia and dysmeno rrhoea are believed to be 8% and 45-97% \nrespectively.1 This high prevalence reflects the diseas e burden in the comm unity. Pelvic pain \nremains the single most common indication for referral to a gynaecology clinic accounting for \n 12\n\n  \n20% of all outpatient appointments. 3;13 Five percent of all new appointments are for CPP. 14 \nPelvic pain has a major impact on health-related quality of life, work productivity and health \ncare utilisation. It is also a major cause of workplace absenteeism. 15 An estimated 158 million \npounds are spent annually on the management of  this condition in th e health service. 16 In the \nUSA, $881.5 million are spent per y ear on its outpatient management. 17 From published \nstudies it is estimated that approximately 40 per cent of all laparoscopies are done for CPP. 3  \n \nBecause CPP can reduce the quality  of life and general wellbeing, th ere is a need to establish \nthe true extent of the problem  by performing a systematic re view of all community based \nprevalence studies. One such review  exists but it has been rest ricted to studies done in UK \nonly. 1 \n \n1.3 Aetiology of chronic pelvic pain \nCPP can have pathologic causes like endometriosis, adhesions, pelvic varices, etc. In addition, \nvarious social and psychological factors ar e reported to be associated with CPP 18 such as \npersonality traits, abuse in childhood or adulthood etc. 19  \n \nThe aetiology of primary dysmenorrhoea has been  the source of considerable debate. Recent \nlaboratory and clinical research have identified  over-production of uterine prostaglandins as a \nsubstantial contributing factor to the pain ful cramps that are the major symptom of \ndysmenorrhoea.20 Prostaglandins are also implicated  in secondary dysmenorrhoea, however \nanatomical mechanisms can also be identified, depending on the type of accompanying pelvic \npathology. 21 Several primary studies, many with conflic ting results, have made an attempt to \nidentify possible predisposing factors for CPP.  Those assessing psychological factors have \n 13\n\n \nbeen previously summarised in a meta-analysis, 19 which, due to, language restrictions in its \nsearch 22;23 and lack of study quality assessment, 24 could not generate robust inferences. \nStudies evaluating physical factors in CPP have not so far been reviewed systematically to our \nknowledge. If the significance of  both physical and psychosoci al factors purported to be \nassociated with CPP can be evaluated reliably, these may be more effectively targeted for \nclinical evaluation, prevention a nd treatment strategies and may help in designing research \nstudies too. \n \n1.4 Anatomy of pain pathway and rationale for nerve ablation \nPelvic pain is poorly understood entity. Descartes originally suggested that pain was a simple \nsignal from peripheral pa in neurons to the brain (the soma tic theory). Eventually it became \nclear that pain is much more complex. The gate  theory proposes that peripheral nociceptive \nsignals can be modulated by neurotransmitters like serotonin and endorphins that can be \nlinked with mood states.\n25 The pain may be evoked by depre ssive states as opposed to direct \ntissue irritation. Thus, interacting psychological and physical factors are likely to be present \nand attempt to separate one from the other is generally unrewarding.26  \n \nAnother theory, the diathesis-stress model, proposes that some patients are at increased risk of \nexperiencing chronic pain due to acquired pre-existing vulnerabilities e.g. history of sexual \nabuse.27 The pelvic viscera receive neurons fro m both sympathetic (thoracolumbar) and \nparasympathetic (craniosacral) systems. The corpus, cervix and proximal fallopian tubes \ntransmit pain through sympathetic fibres that arise from T10-L1. These fibres include neurons \nthat are part of the uterosacral ligaments,28 and eventually merge into the superior hypogastric \nplexus (presacral nerve). The presacral nerve does not receive fibres from the ovaries and \n 14\n\n  \nlateral pelvic structures and l ogically presacral neurectomy, wh ich involves the total removal \nof the presacral nerves lying within the boundari es of the interiliac triangle, could work only \nin midline dysmenorrhoea. \n \nThe lateral pelvis transmits pain via nervi erigentes arising from S2-4. The presacral nerve \ndivides into the hypogastric nerve that form the inferior hypogastric plexus, and this plexus \ndivide into vesical, middle rectal and uterovaginal (Frankenh auser’s) plexuses. \nFrankenhauser’s plexus lies lateral to the uter osacral ligaments and medial to the uterine \narteries and receives pain sens ations only from the corpus a nd vagina. Interruption of these \nnerve trunks by uterosacral nerve ablation, as shown in figure 1.1 may alleviate pain.  \n \nFigure 1.1: Pelvic nerve pathways and sites for laparoscopic uterosacral nerve ablation \n[C= afferent nerve supply of cervix (illustrated on right side of diagram); O= afferent nerve supply of ovary \n(illustrated on left side of diagram); U= afferent nerve supply of uterus (illustrated on right side of diagram). The \npermission to publish this figure has been kindly granted by Blackwell Sciences limited] \n \nInterruption of these nerve pathways has been used to alleviate pain by open abdominal or \nvaginal approach in the past, 29;30 but now this procedure can be performed less invasively via \n 15\n\n \nlaparoscopic approach 31;32 and is often referred to as laparoscopic uterosacral  nerve ablation \nor LUNA in short. This procedure is a topic for evaluation of practice patterns, beliefs and \neffectiveness in this thesis. \n \n1.5 Survey of Practice of LUNA \nOriginally laparoscopic surgical experts were of  the opinion that because of the divergence of \nthe sensory nerve fibres and thei r ganglia as they leave the ut erus, the uterosacral ligaments \nshould be vaporised as close to the cervix as possible. 32 However, recent anatomical studies \nhave demonstrated that the greatest number of fibre bundles are at some distance from the site \nof attachment of the uterosacral ligament to the cervix 33;34.  Hence there is controversy about \nthe optimal site for LUNA. Anatomical studies also suggest that the nerve fibres are dense at a \ndepth of 3-15mm 33, thus the completeness of transection of the uterosacral ligament can also \nbe expected to have an implication for the effectiveness of LUNA.  \nInformation on prevalent variations in the te chniques regarding optimal site and depth of \nLUNA is currently unavailable . A previous survey showed that many UK gynaecologists \nclaimed familiarity with the operative technique of LUNA 35 but it did not explore the \ndifferences in surgical techniques with respect to the site and depth of LUNA. Thus a survey \nto examine the indications and different surgical  techniques of LUNA is needed to establish \npractice patterns. \n \n 16\n\n  \n1.6 Clinicians’ beliefs about effectiveness of LUNA \nClinicians have varying degrees of certainty about effectiveness of treatments. It is ethical to \ninitiate a clinical trial when there is collective clinical equipoise about the effectiveness of the \navailable treatments.36 Prior beliefs are formed from indirect evidence (laboratory studies, \nepidemiology, extrapolation from similar treatments) and direct evidence (clinical trials, \nperhaps of an inconclusive nature). Surveys eliciting dichotomous ‘yes’ and ‘no’ responses to \na question about effectiveness are limited because clinicians’ beliefs about a treatment usually \namount to rather more than just “I believe it is effective” (or the converse). They may believe \nthe treatment to be greatly or marginally beneficial (or harmful). Some may be rather more \ncertain than the evidence apparently warrants, others may be uncertain to a degree that they \nbelieve the treatment may, in the due course, turn out to be either greatly beneficial or \nharmful.  \n \nFormal measurement of beliefs about effectiveness can provide a clearer picture than the \ndichotomous responses. Formal measurements of ‘prior belief’ provide respondents with an \nopportunity to signal the magnitude of the expected effects and the relative probabilities of \neffects of different sizes. However, the published examples of collecting such information are \nsparse, in both obstetrics and gynaecology and in medicine.37;38 \n \nA recent survey has indicated that there is wide variation in the practice and use of LUNA for \ntreatment of CPP among clinicians, suggesting that collective clinical equipoise is present. \nThe technique has been introduced without definite evidence but opinion regarding its use has \nnot yet solidified, as 81% of gynaecologists performing LUNA stated their willingness to \nrecruit patients in a trial to assess effectiveness of LUNA. 35 However, this survey does not \n 17\n\n \nprovide information on distribution of belie fs concerning effectiveness of LUNA in \nalleviating CPP. A structured survey to formally document the range of beliefs on \neffectiveness of this surgical treatment is required.  \n \n1.7 Research Evidence on effectiveness of LUNA \nAn overview of effectiveness of LUNA concluded that there is insuffici ent evidence to guide \ntherapeutic decision-making with regard to LUNA. 39 A systematic review of effectiveness of \nneuroablation undertaken in 2000 found insu fficient evidence to  recommend it in \ndysmenorrhoea.40 It also recommended the need for future randomised controlled trials \n(RCTs). This information needs to be updated in  view of important tr ials that have been \npublished since to ascertain whether the recommendation needs to be changed.  \n \nThe effectiveness of LUNA is currently being a ssessed in a trial. I worked as a research \nfellow coordinating this trial where I have help ed develop and finalise the protocol. This will \nbe presented in the thesis. \n \n1.8 Aims and objectives \nThis thesis had the following objectives:  \n1. To estimate the prevalence of CPP by means of a systematic review \n2. To generate pooled evidence on the aetiology of CPP by means of systematic review, \n3. To undertake a survey of practice concerning LUNA in Europe \n4. To undertake a survey of beliefs concerning effectiveness of LUNA  \n 18\n\n  \n5. To determine the effectiveness of neuroabl ation in CPP by means of a systematic \nreview  \n6. To develop a protocol for a prospective ra ndomised controlled trial to assess the \neffectiveness of LUNA in CPP \nThese objectives are formulated as structured questions in table 1.1 \nTable 1.1: Structured questions for each chapter of this thesis \nChapter \nnumber \nPopulation Interventions / risk \nfactors \nOutcomes Research \ndesigns \nSection A: Prevalence and aetiology of CPP \n2 Women at risk Prevalence by \nrepresentativeness of \nstudies \nDysmenorrhoea \nDyspareunia \nNoncyclical pelvic pain \n \n \nSystematic \nreview (SR) of \nobservational \n(cross sectional \nor longitudinal) \nstudies \n3 Women at risk General (demographic) \nfactors  \nGynaecological/ obstetric \nfactors  \nPsychological and social \nfactors \nDysmenorrhoea \nDyspareunia \nNoncyclical pelvic pain \n \n \nSR of \nobservational \n(cohort, case-\ncontrol or cross \nsectional) studies \nthat provide \ncomparative \ninformation on \npresence of risk \nfactors in \nwomen with   or \nwithout CPP \nSection B: The Practice and beliefs concerning LUNA \n4 Gynaecologists \nin the UK and \nrest of Europe \nStructured questionnaire  Indications and techniques \nfor LUNA across Europe \nSurvey \n5 Gynaecologists \ncollaborating in \nLUNA trial \nStructured questionnaire  ‘Prior beliefs’ on \neffectiveness of LUNA \nSurvey \nSection C: Effectiveness of neuroablation \n6 Women \nundergoing \nlaparoscopy for \nCPP \nNeuroablative procedures \n(LUNA or presacral \nneurectomy [PSN]) versus \nno neuroablation \nPain relief  \nAdverse effects \nCochrane SR \n7 Women with \nCPP who need \ndiagnostic \nlaparoscopy \nLUNA versus No LUNA \nduring laparoscopy  \nImprovement in CPP, \nquality of life and sexual \nfunction \nMulticentre \nrandomised \ncontrolled trial \nprotocol \nLUNA= Laparoscopic uterosacral nerve ablation; CPP= chronic pelvic pain; SR= systematic \nreview \n 19\n\n \nSECTION A: PREVALENCE AND AETIOLOGY OF CHRONIC \nPELVIC PAIN \n \nIn this section, I summarise the evidence on pr evalence and aetiology of chronic pelvic pain \nwith systematic reviews of relevant studies in the following chapters: \n \nChapter 2. Worldwide prevalence of chronic pelvic pain: A systematic review and meta-\nanalyses \n \nChapter 3: Factors predisposing women to chronic pelvic pain: A Systematic Review \n \n 20\n\n  \nCHAPTER 2: WORLDWIDE PREVALENCE OF CHRONIC PELVIC \nPAIN: A SYSTEMATIC REVIEW AND META-ANALYSES \n \n 21\n\n \n2.1 ABSTRACT \nObjective \nA systematic literature review was performed to  ascertain the prevalence of CPP according to \nthe type of pain and to explore reasons for variation in its rates. \nMethods \nMedline (1966 to 2004), Embase (1980 to 2004) , PsycINFO (1887 to 2003), LILACS (1982 \nto 2004), Science Citation index and CINAHL (Ja nuary 1980 to 2004) were searched to find \npotentially eligible studies. Hand searching of re ference lists of the relevant studies was also \ncarried out. Studies were considered if they had non-pregnant wo men without cancer and \nother specific disorders participating in survey s about rates of CPP. There were 178 studies \n(459975 participants) in 148 articles. Of these,  106 studies were ( 124259 participants) on \ndysmenorrhoea, 54 (35973 participants) on dy spareunia and 18 (301 756 participants) on \nnoncyclical pain.   Two reviewers, using a piloted fo rm, extracted data independently on \nparticipants’ characteristics, studies’ methodological quality and rates of CPP. \nResults \nThere was significant variation among rates of all three types of CPP. Metaregression analysis \nshowed that this heterogeneity was mainly due to non-representativeness of study sample and \ninadequacy of study methods. Meta-analysis of rates amongst high quality studies with \nsamples representative of general population showed that prevalence of dysmenorrhoea (12 \nstudies) was 59% (95% CI 49.1-71%, heterogeneity p<0.001), of dyspareunia (11 studies) \nwas 13.3% (95% CI 8.8-20.3%, heterogeneity p<0.001) and of noncyclical pain (3 studies) \nwas 10.4% (95% CI 9.1-25.7%).   \n 22\n\n  \nConclusion \nThe variation in rates of CPP worldwide is explained by variable study quality. High quality \nliterature revealed a high burden of disease. \n 23\n\n \n2.2 INTRODUCTION \nThere is a need to establish the true extent of CPP for policy makers to consider in resource \nallocation and health care planning. In additi on, these basic data are necessary to inform \ndesign of other research in this  condition, like qualitative studies  to establish well being and \noverall quality of life, gene tic and environmental epidem iology to assess aetiology, and \nstudies aimed at the developmen t of new treatment strategies 41. The epidemiological features \nof CPP have been generously reported in the wo rldwide literature. Majority of the studies are \nlimited by small sample size and hence their in ability to estimate prevalence precisely. The \nneed to summarise this, however, has received scant attention42.  \n \nA systematic literature review was performed to ascertain the geographical distribution of \nCPP, its prevalence according to the type of pain, and its variation within subgroups defined \nby age and development status of the country of origin whilst taking into account the quality \nof the studies. \n \n2.3 METHODS \nOur systematic review followed a protocol developed using widely recommended \nmethodology. \n43;44 \n \n2.3.1 Data sources \nWe searched general bibliographic databases: Medline (1966-2004), Embase (1980-2004) and \nPSYCHINFO (1887-2004). We also searched specialist computer databases: LILACS \n 24\n\n  \n(Literatura Latinoamericana y del Caribe en Ciencias de la Salud 1982 to 2004), CINAHL \n(January 1980 to 2004) and SCISEARCH (1974-2003).  \n \nOur search term combination for electronic databases, based on published advice, was as \nfollows: MeSH headings, text words and word variants for “pelvic pain”, “dysmenorrhoea”,  \n“dyspareunia”, and “low abdominal pain” were combined with terms like “prevalence”, \n“community survey” and “incidence”. These were combined with terms representing relevant \nstudy designs e.g. cross-section, survey etc. according to recent recommendations45 for \nsearching and the search was restricted to human and female (appendix 2.1). We also hand \nsearched the bibliographies of all relevant reviews and primary studies to identify cited \narticles not captured by electronic searches. The search did not have any language restrictions. \n2.3.2 Study selection  \nStudies on CPP were selected using the following predefined criteria: \nParticipants: Non-pregnant women without cancer or other specific diseases participating in \nsurveys about rates of CPP. \nOutcome: There is lack of consensus on the definition of CPP in the published literature.46 \nWe used a definition based on duration and nature of pain (constant or intermittent, cyclical or \nnoncyclical pain, that persisted for 3 months or more8) and included three types: cyclical pain \nduring menstruation (dysmenorrhoea), deep dyspareunia and noncyclical pelvic pain. Studies \nwere included in the absence of information on duration of pain as long as it was explicit that \ncases of acute pain were excluded. \nStudy design: Cross sectional studies that reported the prevalence of CPP. \n \n 25\n\n \n2.3.3 Data extraction and quality assessment \nTwo reviewers extracted data independently, using a piloted form, on participants’ \ncharacteristics, study quality and rates of CPP. Data on studies not published in English were \nextracted by people with a medical background with command of the relevant language. We \nextracted information on whether studies evaluated dysmenorrhoea, dyspareunia and \nnoncyclical pain symptoms individually or in combination. In some studies the existence of \nmultiple symptoms amongst individuals could not be evaluated separately due to the structure \nof their questionnaires used and their manner of reporting and were excluded.  \n \nThe methodological quality of all selected papers was assessed to evaluate internal validity \nusing the following attributes43: (a) Study design to determine if CPP assessment had been \nperformed prospectively to minimise recall bias; (b) Adequacy of sampling by assessing \nwhether recruitment of participants was random or consecutive or a convenience sample; (c) \nSufficiently high response rate (>80%); (d) Use of a validated  measurement tool to ascertain \nCPP as this ensures that participants’ responses are a true representation of the underlying \ncondition; (e) Sample size calculation so as to ascertain prevalence reliably. The studies were \nclassified into high and low quality groups based on compliance with 3/5 quality criteria or \nmore. Representativeness of the sample for general population (source of sample) was \nconsidered separately to methodological quality as this relates to external validity. This \ndistinction is important because internally valid studies of women attending hospitals or for \nprivate health care checks may not be biased but they are less useful due to sampling of \nnongeneralisable population groups. \n \n 26\n\n  \nNumerators and denominators were extracted or estimated from each study for computing \nrates and confidence intervals (CI). In our review, prevalence measured how many women \nhave CPP at a single point in time, i.e. point prevalence.47 Period prevalence, based on the \nnumber of women developing CPP during a defined period of time, was reported only in a \nfew studies.  \n \n2.3.4 Data synthesis \nFor each study, we computed prevalence rates and their 95% CI according to the three \ndifferent types of CPP. Rates of the different CPP were mapped to depict the variation in \nprevalence by country of origin. Heterogeneity was explored in the rates of CPP graphically \nusing forrest plots of point estimates of rates and their 95% CI and statistically using \nCochrane Q. Meta-regression explored if heterogeneity could be explained by variations in \ncountries’ development status, participants’ average age, representativeness of the sample and \nmethodological quality of the included studies.48 For development status we used the United \nNations classification (developed, less developed and least developed) for countries. Study \nquality was assessed separately for individual items and scores. We performed both univariate \nand multivariate meta-regression analysis. Only high quality, representative studies were \nincluded in the final meta-analysis. Thus none of the hospital-based studies are included in the \nmeta-analyses as they were not representative of the general population. Meta-analyses of log \nrates were performed weighting each study by the inverse of its variance49 using the random \neffects method50 (Stata 8 software) and the output was exponentiated. Publication bias was \nexamined for, by plotting log rates versus their corresponding variances in a funnel plot. \nFunnel asymmetry was tested for using Egger’s test51 and Begg’s test.  \n 27\n\n \n2.4 RESULTS \nLists of included studies (appendix 2.2) as well as each included study’s salient features; \nmethodological quality and accuracy data are given in Appendices 2.3,2.4 and 2.5 (in the \naccompanying CD ROM).  \nFigure 2. 1: Study selection for systematic review on prevalence of chronic pelvic pain \nTotal citations identified from electronic searches 1226\nPapers retrieved for detailed evaluation: 225\n1001 Citations excluded after screening abstract\nPapers excluded: 109\nNo/ Insufficient /unclear data 5 \nNot a primary data source 20\nNot on prevalence of pelvic pain 50\nDuplicate data 9\nUnobtainable3\nStudy performed in : pregnant/postnatal women 8\n: cancer 4 \n: other specified disorders 7\n: case-control study/case report  4\nPrimary papers included in systematic review: 148\n178 studies (some papers  report more than one outcome/study):  \n106 – dysmenorrhea\n54 - dyspareunia \n18 -noncyclical CPP \nSearching of reference lists: 32\n 28\n\n  \nThe electronic search yielded a total of 1226 citations (figure 2.1). On examination of titles \nand abstracts, 228 were found to be potentially relevant and their full papers were obtained. \nThe reference lists of these revealed 32 further citations. After reviewing these, 109 papers \nwere excluded. The remaining 148 papers met the inclusion criteria, which provided data on \n459972 participants. 29 studies overlapped and reported more than one outcome. There is \nvery little data (1/143 papers) available from the least developed countries. Study quality \nassessment (shown in figure 2.2 below) revealed deficiencies in many areas of methodology: \nTwo (1.2%) studies met all five high quality criteria, 12 (7.1%) met 4/5 criteria. There were \n47 studies (27.8%) that met three or more quality criteria.  \nFigure 2.2: Quality of studies included in systematic review on prevalence of chronic \npelvic pain (Data presented as 100% stacked bars; figures in the stacks represent number of studies).  \n \n \n \n \nThe data on prevalence of CPP in included studies is summarised in figures 2. 3 – 2.5. Figure \n2.3 depicts the range of the number of studies and the percentage of pelvic pain found in those \n 29\n\n \nstudies. Figure 2.4 shows the scatter of prevalence of the different types of pelvic pain with \ntheir confidence intervals. Epimaps in Figure 2.5 depict the available data on worldwide \nprevalence of different types of chronic pelvic pain by countries. \n \nFigure 2.3: Prevalence rates of different types of chronic pelvic pain amongst included \nstudies \n2\n4\n6\n8\n10\nNoncyclical pain (n=18)\n0 1 02 03 04 0 5 06 07 08 09 0 1 0 0\nPrevalence of Chronic Pelvic Pain (%)\n2\n4\n6\n8\n10 Dyspareunia (n=54)\n0\n0\n2\n4\n6\n8\n10\nDysmenorrhoea (n=106)\n \n2.4.1 Dysmenorrhoea \nThe prevalence rates ranged from 1.7%17 to 93.3%52 in 106 studies including 125249 women. \nPrevalence rates for cyclical pelvic pain in the UK reported were between 45% (12% \nreporting severe)53 to 97%54(14% severe) for any dysmenorrhoea in community based studies \nand between 41-62% in hospital based studies55;56. In other European countries it was \nsimilar.15;57 The lowest prevalence was reported in Bulgaria (8.8%) in women hospitalised \nwith adnexitis between the ages of 19-41 years and the highest was in Finland (94%) in girls \n 30\n\n  \naged 10-20 years.52 There was heterogeneity and the funnel plot for dysmenorrhoea was \nasymmetrical (Begg’s test P =0.02; figure 2.6) but not for representative studies (P=0.333) \nMetaregression showed validated measurement tool to be a significant factor to explain \nheterogeneity but not study quality score, representativeness, age< 25 years or development \nstatus of the country (developed vs. less developed vs. least developed). The prevalence of \ndysmenorrhoea in 54 representative studies was 46.7% (42.0-51.8%) as shown in figure 4. In \n12 high quality representative studies, the pooled prevalence was 59.1 % (95% CI 49-71%) \n \nFigure 2. 4: Data synthesis of studies on prevalence of different types of chronic pelvic pain.  \n(See methods for details of meta-analysis. Heterogeneity p=<0.001 for all meta-analyses) \n \n \n 31\n\n \n2.4.2 Dyspareunia \nThe prevalence rates ranged from 1.3% 58 to 45.7% 59 in 52 studies including 35973 women. \nThe rates of dyspareunia varied from 1.1% in Sweden 60 to 45% 59 in US studies. In 26/52 \nrepresentative studies, the overall prevalence of dyspareun ia was 10.3% (95% CI 7.2-13.4%, \nheterogeneity p<0.001). In 11 high quality repr esentative studies, the prevalence of \ndyspareunia was 13.3% (95% CI 8.8-20.3%, heterogeneity p<0.001). Studies were markedly \nheterogeneous (P=0.000) and the funnel plot for dyspareunia was asymmetrical (Begg’s test P \n=0.001; figure 2.6) but not in representative st udies (P=0.227). The representativeness of \nsample provided the main explanation for heter ogeneity that was statistically significant in \nmeta-regression analysis (appendix 2.6). Age under 60 was not a significant factor in \nmetaregression (P=0.15).  \n \n2.4.3 Non-cyclical pelvic pain \nThe prevalence rates ranged from 4.0% 61 to 43.4%62 in 17 studies including 299740 women. \nThe funnel plot for noncyclical pelvic pain was asymmetri cal (Figure 2.6; Begg’s test \nP=0.048; figure 2.6) but not for representative studies (Begg’s test P=0.88). Two recent high \nquality studies stated a 3 month prevalence of  15% in women aged 18 -50 years in the USA 17 \nand 24% in ages be tween 12-70 in the UK. 12 In less developed countri es in South East Asia \nthe prevalence rates varied fr om 5.2% in India, 8.8% in Pakistan to 43.2% in Thailand. 62 The \noverall prevalence of noncyc lical pain was 13.1% (95%CI  7.7-22.4%, heterogeneity p< \n0.001) in 7 representative studies. The prevalen ce of noncyclical pelvic pain in two high \nquality representative studies was 10.4% ( 95%CI 6.7-16.2%, heterogeneity p<0.001). The \nmetaregression revealed that prospective de sign, adequate sampling strategy, sample size \n 32\n\n  \nestimation and high quality studies tended to describe lower prevalence of noncyclical pelvic \npain though none of these were significant.  \n \n \nFigure 2.5 Epimaps of worldwide prevalence of different types of chronic pelvic pain \n(dysmenorrhoea, dyspareunia and noncyclical pelvic pain respectively) \n 33\n\n  \n 34\n \n 34\n\n   \n \n \n35\n \n 35\n\n \n 36\n\n\n  \n \nBegg's funnel plot with pseudo 95% confidence limits\nlogr\ns.e. of: logr\n0 .2 .4\n-4\n-3\n-2\n-1\n0\nlogr\ns.e. of: logr\n0 .5 1\n-6\n-4\n-2\n0\n2\nlogr\ns.e. of: logr\n0 .5 1\n-6\n-4\n-2\n0\n2\nDysmenorrhoea\nDyspareunia\nNoncyclical pelvic pain\n \nFigure 2.6: Funnel plots of the three types of pelvic pain prevalence studies \n \n2.5 DISCUSSION \nThis is the first systematic re view of the worldwide prevalence  of CPP. It pooled rates of \nvarious types of CPP in high quality representative studies. Development status of the country \ndid not affect the high rates of pain observed.  The variation in rates of CPP worldwide is \nexplained by variable study quality. High quality literature revealed a high burden of disease \nfor dysmenorrhoea and dyspareunia. \n \n 37\n\n \nWe believe that the findings of our study are valid as our review methodology was rigorous. \nA prospective review protocol was used and a concerted effort made to identify all the \navailable evidence without language restriction. We made concerted efforts to report this \nsystematic review as suggested by the MOOSE consensus statement (see table 2.5).63 Both \nthe methodology and the rates of CPP varied among the included primary studies and \nexplored the reasons for variations. For meta-analysis we included only high quality \nrepresentative community studies in an attempt to summarise the prevalence in the general \npopulation. This review represents the best available evidence on the estimates of the \nprevalence of CPP at the time of writing and provides the best information available for \ntargeting services at women suffering from pelvic pain.  \n \nThe variation in geographical distribution may be related to study ch aracteristics, study \nquality, age groups included and definitions used rather than intrinsic differences between the \nprevalence of CPP between the different populati ons. Other plausible e xplanations might be \ndifferences in the prevalence of sexually transm itted infections, availa bility of medical and \nother resources or cultural differences. A lthough we have included studies from 1924 \nonwards, majority of the stud ies are from 1980 onwards. Th e population demographics are \nunlikely to have undergone major changes over th is period, making the studies relevant to \ncurrent populations. Substantial differences or ev en complete absence of definitions, together \nwith differences in age ranges of the populations studied, complicate the interpretation to a \ngreat extent.  \n \nThe information on which groups have increased rate of dysmenorrhoea, dyspareunia have \nimplication for provision of services to policymakers in terms of provision of improved \n 38\n\n  \naccess for these women to health care resources as well as the development of appropriate \ntreatment protocols. Future epidemiological studies should ideally be prospective, with \nexplicit definitions of the outcome and representative of the general population. The survey \nshould use the validated measurement tools for validity and comparability of the results. \n 39\n\n \nCHAPTER 3: RISK FACTORS IN CHRONIC PELVIC PAIN: A \nSYSTEMATIC REVIEW AND META-ANALYSES \n 40\n\n  \n3.1 ABSTRACT \nObjective \nTo evaluate the factors  predisposing women to chronic pelvic pain, a common chronic \ncondition. \nMethods \nSystematic review of all relevant studies without language restrictions was carried out. \nStudies were identified without language restrictions through Medlin e, Embase, PsycINFO, \nCochrane Library, SCISEARCH, conference  papers and bibliographies of retrieved primary \nand review articles (upto April 2004). \nTwo reviewers independently extracted  data on study characteristics, quality and  results. \nExposure to risk factors was compared between women with and without pelvic pain. Results \nwere pooled within subgroups defined by type of pain and risk factors. Data were pooled to \nproduce summary estimates of Peto odds ratio (OR) or standardised mean differences (SMD). \nResults \nThere were 122 studies (in 112 articles) of which 63 (64,286 women) evaluated 54 risk \nfactors for dysmenorrhoea, 19 (18,601 women) evaluated 14 risk factors for dyspareunia and \n40 (12,040 women) evaluated 48 factors for noncyclical CPP. Age less than 30 years, low \nbody mass index (BMI), smoking, early menarche (<11 years), longer cycles, longer duration \nof bleeding or heavy menstrual flow, nulliparity, premenstrual syndrome, sterilisation, pelvic \ninflammatory disease, sexual assault, emotional difficulties, psychological symptoms, suicidal \ntendency and somatisation were associated with increased risk of dysmenorrhoea. Younger \nage at first childbirth, exercise and oral contraceptives and were associated with reduction in \n 41\n\n \nthe risk of dysmenorrhoea. Age less than 50 years, peri/post menopausal state, PID, sexual \nabuse, anxiety and depression were found to be associated with dyspareunia. Drug/alcohol \nabuse, miscarriage, heavier menstrual flow, PID, previous caesarean section, pelvic \nadhesions/other pathology, childhood physical or sexual abuse, lifetime sexual abuse, anxiety, \ndepression, hysteria, psychosomatisation were associated with an increased risk of \nnoncyclical pelvic pain. \nConclusion \nKey gynaecological and psychosocial factors associated with CPP should be targeted in \nclinical evaluation of women with this symptom to individualise their management. \n 42\n\n  \n3.2 INTRODUCTION \nThere is wide variation in clinical evaluation of women with CPP. In some countries, like the \nUK, diagnostic laparoscopy is the standard investigation on referral to gynaecologists. \nLaparoscopy is negative in over 50% of cases, 3 so considering its invasive nature many \nclinicians reserve it for evaluation when non-invasive options have been exhausted.18 Thus in \nsome countries, like in mainland Europe, empirical treatment is the standard initial \nmanagement. 64 This variation in practice is in also due to uncertainty about effectiveness of a \nlot of available treatments to alleviate pathologic causes. 65-67 An initial strategy to uncover \nand treat pathologic causes like pelvic varices, adhesions and endometriosis first is not \nnecessarily better than psychological management first. More fundamentally, the extent to \nwhich these pathologies are causally related to pain is itself uncertain as they overlap with \npsychosocial factors in a majority of CPP cases.68;69 Even laparoscopy is believed to have \nbeneficial effects through psychological mechanisms.70;71 A better understanding of the \nrelative contribution of various pathological, social and psychological factors to CPP19 may \nbe helpful in clinical evaluation as well as in the development of prevention and treatment \nstrategies and the design of future studies. \n \nA number of primary studies have sought to identify predisposing factors for CPP but often \nwith conflicting results. A previous meta-analysis 19has summarised the evidence on social \nand psychological factors, but language restrictions in its search  and no assessment of the \nquality of studies included, 24 potentially limit its findings. No systematic review of the \ninfluence of physical and environmental factors in CPP has so far been undertaken. Hence a \ncomprehensive systematic review of all studies was performed to evaluate risk factors for \nCPP. \n 43\n\n \n3.3 METHODS \nWe first developed a protocol using widely recommended methods  for systematic reviews of \nobservational studies.44;63 \n3.3.1 Data sources \nWe searched general bibliographic databases: Medline (1966-2003), Embase (1980-2003) and \nPSYCHINFO (1887-2003).  We also searched specialist com puter databases: the Cochrane \nLibrary (2003:1) and SCISEARCH (1974-2003).  Our search term combination for electronic \ndatabases, based on published advice,72 was as follows: MeSH headings, text words and word \nvariants for “chronic pelvic pain”, “dysmeno rrhoea”,  “dyspareunia”. Relevant terms for \naetiological factors e.g. causal, odd s ratio, relative risk etc. were used to combine with terms \nrepresenting relevant study designs e.g. cohort, risk, case control studies,  etc. and the search \nwas restricted to human and fe male (see appendix 2 for details). We also hand searched the \nbibliographies of all relevant reviews and primary studies to identify cited  articles not \ncaptured by electronic searches. \n3.3.2 Study Selection \nStudies on CPP that included a comparativ e group without pelvic  pain and provided \ninformation on exposure to any risk factor were selected using the following criteria: \nParticipants: Women at risk. \nRisk factors (exposures) : General factors : Age, race, body mass index, smoking, \noccupational exposures, socio-economic stat us, education, sport activities etc. \nGynaecological/obstetric factors: contraception, age at menarche, duration of menstrual flow, \nlength of menstrual cycle, premenstrual sy mptoms, infertility, history of abortion or \nmiscarriage, parity, age at birth of first child , previous caesarean section, previous pelvic \n 44\n\n  \ninflammatory disease (PID), presence of pelv ic adhesions, varices, endometriosis, menopause \netc. Psychological and social factors: history of childhood or lifetime physical, psychological \nor sexual abuse, anxiety, de pression, borderline syndrome, psychosomatic symptoms, alcohol \nor drug abuse, unsatisfactory fam ily relationship, history of deat h or divorce of parent at an \nearly age, alcoholism in parent, disturbed puberty or childhood etc.  \nOutcomes: Chronic (duration 3 months or more ) noncyclical pain, menstrual pain \n(dysmenorrhoea) and pain related to intercourse (dyspareunia) localised in the lower abdomen \nand pelvis. \nStudy designs: Observational (cohort, case-control or cross sectional) studies that provided \ninformation on the association of risk factor s with CPP were incl uded. Studies without \ncomparative information on risk factors were excluded. \n \nStudies were selected  in a two-stage process. One of us (PML) scrutinised  the citations \ndownloaded from the electronic searches and obtained full manuscripts of all citations  that \nwere thought to meet the predefined selection criteria or if there was uncertainty whether they \nwere eligible for inclusion. Final  inclusion or exclusion decisions were made when two of us \n(PML and LM) examined  these manuscripts. In cases of dup licate publication we used all \nreports to assess study characteris tics and quality, but only selected  the most recent and \ncomplete versions for results. We applied no la nguage restrictions. Two of us (PML and LM) \nindependently assessed English manuscripts. People who had command of the language to \nallow data extraction assessed manuscripts in other languages (Chinese, Bulgarian, French, \nGerman and Japanese). We resolved  any disagreements about inclusion  or exclusion by \nconsensus or arbitration by a third reviewer (KSK). \n 45\n\n \nInformation on characteristics of exposures and outcomes we re extracted. Some studies \nprovided information on more than one outcome. For each of noncyclical pain, \ndysmenorrhoea or dyspareunia, we extracted da ta on separate forms.  Wherever possible, \nexposure data and numbers of women with a nd without CPP were used to construct 2×2 \ntables. In studies where the data on exposur e were continuous, we abstracted means and \nstandard deviation and numbers in groups with and without CPP. In some studies, where both \nof these data was absent, significance (p) values  or correlation coefficients if quoted were \nextracted. We pilot tested the data  extraction form on primary studies related to dyspareunia \nusing two reviewers (PML and LM). Overall, the observer ag reement regarding the various \ncomponents of the data extraction form was 90-100%. We attempted to obtain missing data by \ncontacting authors via email or post wherever possible.  \n3.3.3 Methodological quality assessment \nWe assessed all manuscripts that met the selection  criteria for quality. We defined quality as \nthe confidence that the study design, conduct and analysis minimised bias in  the estimation of \nthe effect of exposure to a risk  factor on CPP. Our quality items were based on existing texts \nand checklists.44;63 \nBias can be associated with retrospective designs, non-consecutive or non- random participant \nrecruitment, lack of blinding of assessors, par tial verification of exposure to risk factors and \noutcome, overlooking temporality and lack of matc hing or adjusting for confounding factors. \nWe considered a study to be of good quality  if it used 1) prospectiv e design 2) consecutive or \nrandom participant recruitment 3)  ascertainment of exposures using validated instruments, 4) \nascertainment of outcome by clinical evaluati on with or without laparoscopy, 5) temporal \nrelationship between exposure and outcome and 6) controlled for confounding factors. We \nclassified studies into high or lo w quality categories by whether or not they fulfilled three or \n 46\n\n  \nmore of the above six quality criteria. This is arbitrary cut off and not yet validated for non \nrandomized studies. \n \n3.3.4 Data synthesis \nWe tabulated information from each study stra tified according to the three prespecified \noutcomes (noncyclical pelvic pain, dysmenorr hoea and dyspareunia). Results were computed \nseparately for dichotomous and continuous data. For dichotomous data, effects in individual \nstudies were assessed using standard Mantel Haenszel techniques, giving Peto odds ratios and \nconfidence intervals. 73 For continuous outcomes, the outco me measure of interest was the \nStandardised mean difference (SMD), the diffe rence in means divided by the pooled standard \ndeviation, which was used to allow the synthesis of data from studies where different scales \nwere used.74 This method assumes that differences in standard deviations in the studies arise \nfrom differences in the scales rather than differences in popul ation. However, even if this \nassumption is invalid, a consistent effect of an exposure between studies should still give \nqualitatively similar effects in all studies. In order to combine studies which assessed the \nsame factors, but where some studies used co ntinuous and some used dichotomous variables, \nwe used the standard correction factor of π/√3 to convert from SMD to log odds ratio.\n73 \nResults were displayed graphica lly using odds ratio (Forrest) pl ots with twin (continuous and \ndichotomous) scales where appropriate and he terogeneity between trials assessed using \nstandard techniques.74 In order to allow somewhat for the possibility of false positive results \narising out of multiple testing, 99% confidence intervals were used in all plots. \nStudies within each outcome were subgrouped according to risk factors and further according \nto control groups (pain free or with other pain). We also stratified by study quality. We \n 47\n\n \nassessed heterogeneity of individual effects within subgroup of studies graphically (using OR \nplots) and statistically (using chi square test) to help us decide how to proceed with \nquantitative synthesis.75;76 We explored for possible sources of heterogeneity by meta-\nregression analysis77;78 using various explanatory variables defined a priori including age and \nstudy quality. When a variable was not explicitly mentioned, it was treated as \"no\" in the \nmeta-regression analysis.  \n \n3.4 RESULTS \n3.4.1 Literature identification, study characteristics and quality \nFigure 3.1 summarises the process of literature identification and selection. We identified \n5326 citations, from which 122 studies were selected for this review. 63 studies (64,286 \nwomen) evaluated dysmenorrhoea, 15;52;55;61;79-137 19 studies (18,601 women) evaluated \ndyspareunia. 96;111;136-152 and 40 studies (12040 women) evaluated noncyclical pelvic \npain.65;68;96;108;136;138;140;142;152-181 \n \nSummaries of each study’s salient features are given in Appendix 3 (3.5-3.13 in CD ROM). In \n28/40 (70%) studies on noncyclical pelvic pain, 29/63 (46.03%) on dysmenorrhoea and 13/19 \n(68.42%) studies on dyspareunia 3 or more quality criteria were satisfied. Multivariable \nmetaregression analysis showed that sexual abuse was not associated with a particular type of \nCPP. In this analysis, poor quality studies had more prominent associations between abuse \nand pelvic pain than good quality studies (p=0.02). Multivariable analyses did not alter the \nsignificance of quality. Funnel\n plots of the analyses of abuse and pelvic pain showed \nasymmetry. \n 48\n\n  \nFigure 3.1: Study selection process for systematic review of studies of \npredisposing factors for chronic pelvic pain (see appendix for list of excluded \nstudies) \n \nTotal citations identified from electronic searches to capture articles \non risk factors in chronic pelvic pain (n= 5563) \nCitations excluded after screening \ntitles and/ or abstracts (n= 5361) \nArticles retrieved for detailed evaluation (n=202) \nFrom electronic search (n=153) \nFrom reference lists \n(n=49) \nArticles excluded    (n=91) \nPart duplicate data   (n=7) \nData not extractable  (n=3) \nNo control group (n=8) \nNo group without exposure to risk factor (n=10) \nNot on pelvic pain (n=13) \nUnobtainable (n=3) \nNo risk factors studied (n=6) \nComment/case report/letter (n=13) \nReview articles \n(n= 28)\nArticles included in systematic \nreview (n=111)\n  \nSome of these report several \nstudies on different types of \npain\n \nStudies included (n=122): \nPelvic pain (n=40) \nDysmenorrhoea (n= 63) \nDyspareunia (n= 19) \n \n 49\n\n \n \nFigure 3.2: Methodological quality of studies included in the systematic review of risk \nfactors for chronic pelvic pain  \n(Data presented as 100% stacked bars; figures in the stacks represent number of studies). \n \n76\n31\n52\n84\n59\n14\n46\n91\n70\n38\n63\n108\n0% 20% 40% 60% 80% 100%\nControl for\nconfounding\nTemporality\nAscertainment of\noutcome\nAscertainment of risk\nfactor\nRecruitment of subjects\nProspective study\ndesign\nAdequate\nInadequate\n \n \n 50\n\n \n \n \n51\n  \nFigure 3.3: Metanalyses of risk factors associated with dysmenorrhoea \n(All multiple studies are heterogeneous, *** p<0.0001; **p<0.001; p<0.01) \n\n \n \n \nFigure 3.4: Metanalyses of risk factors associated with dyspareunia \n(All multiple studies are heterogeneous, *** p<0.0001; **p<0.001; p<0.01) \n3.4.2 Risk factors for CPP \nThin (BMI<19) women, less than 30 years, nulliparous, smokers, ones who had early \nmenarche (<12 years), longer cycles / duration of bleeding, irregular or heavy menstrual flow, \npresence of premenstrual symptoms, PID, sterilisation and history of sexual assault presented \nmore frequently with dysmenorrhoea (figure 3.3). The risk of dysmenorrhoea increased with \nthe number of cigarettes smoked per day (p<0.05 by trend test).89;182. Use of oral \ncontraceptives, physical exercise, being married or in a stable relationship and higher \nDyspareunia was commoner in women less than 50 years old, history of circumcision, PID \nand peri/postmenopausal. Women with dyspareunia reported anxiety, depression and sexual \nassault more frequently (figure 3.4).  \n \n 52\n\n  \nNoncyclical CPP was associated with numerous general, gynaecological and obstetric factors, \nabuse and psychological morbidity notably previous miscarriage, longer menstrual flow, \npresence of endometriosis, PID, caesarean section scar, pelvic adhesions, childhood physical \nor sexual abuse, lifetime sexual abuse or any abuse, anxiety, depression, hysteria and \nsomatisation (figure 3.5). On subgroup analysis, it was found that the abuse was more \nstrongly associated with pelvic pain when the comparison group was painfree than when the \ncontrols had other pain like backache, headache etc. On comparing women with CPP (without \nand with obvious pathology) with pain free groups, across studies for psychological morbidity \n(depression, anxiety, neuroticism and somatisation), it was noted that psychological morbidity \nwas more in women with pelvic pain irrespective of presence or absence of pelvic pathology \non laparoscopy (p=0.03).  \n \n 53\n\n \n \nFigure 3.5: Metanalyses of risk factors in noncyclical pelvic pain \n(All multiple studies are heterogeneous, *** p<0.0001; **p<0.001; p<0.01) \n 54\n\n  \n3.5 DISCUSSION \nThis review found key gynaecological and psychosocial factors that will be useful in clinical \nevaluation of CPP. Presence of pelvic pathology, history of abuse and coexistent \npsychological morbidity showed consistent associations with CPP. \nThis systematic review comprehensively evaluated over 60 risk factors in 122 studies related \nto CPP. It was rigorously carried out with an extensive literature search without foreign \nlanguage restrictions and with formal assessment of study quality to evaluate bias. It met \nquality criteria laid down in the MOOSE statement.63 It generated information on strength and \nconsistency of associations of various risk factors with various types of CPP, so we could \nconsider evaluation of some causal criteria. The variation and the poverty  of methodological \nquality of the included studies have implications for the validity of our findings. Retrospective \nstudies are subject to incomplete or selective recall of previous events41. The exposure \ncomparisons might not have been appropriate in some studies, e.g. non-sexual abuse group \nmay actually be a non-sexually abused group of women who have experienced physical or \npsychological abuse, possibly increasing psychosocial distress and diminishing clinically \nrelevant differences between the groups.183;184 Other concerns relate to the use of non-\nstandard measurement tools with questionable validity or reliability to discriminate between \nwomen with and without CPP. Ascertainment bias may arise by selecting control groups from \nwomen consulting for other conditions in the same setting, who did not have assessment like \nlaparoscopy, so in them presence of pathology could not be assessed. An explicit definition \nfor CPP was not uniformly used. These factors reduce the ability to confidently investigate \ncausation.\n46 However, this is the best available evidence of the risk factors for CPP. \nBias in reporting is a potential problem as studies may have looked at the interaction of \nseveral risk factors with CPP but published only those that were interesting or statistically \n 55\n\n \nsignificant. This could, conceivably, introduce bias in both directions—that is, analyses are \nprobably equally likely to be published whether or not a particular factor indicates an \nabnormally high or an abnormally low risk. We decided to combine odds ratio and mean \ndifferences for risk factors where both types of results were expressed. This was done to avoid \nloss of strength of combined information as well as to avoid results from two analyses that \ncould conflict and lead to an erroneous conclusion.73 \n \nCertain study design features may impinge on the generalisability of our findings.41 Women \nincluded in many of the community based studies of dysmenorrhoea did not have detailed \ninvestigations to rule out pathology and so they cannot be classified strictly either as primary \nor secondary dysmenorrhoea.84 The need for imaging or laparoscopy to identify pathology in \nhospital setting means that in some studies, 99;118;185 associations between risk factors and CPP \nmay be due to differences in health care seeking behavior and referral patterns compared to \ncommunity settings.41 We feel that the associations observed for abuse, pathology and \npsychosocial morbidity are generalisable, because these were consistent across the studies \nfrom different geographical and age groups. \nAbuse was consistently and strongly associated with all types of CPP highlighting a possible \ncausal role for it. Similar effect of these exposures on controls with other pain in contrast with \npainfree controls reflects the complex psychological interactions involved in the pain process \nor pathway.  \n \nThe mechanisms through which various pathologies might cause pain are not entirely clear. \nPelvic inflammatory mediators and congestion may lead to all kinds of CPP in PID. \nPremenstrual symptoms are often associated with ovulatory cycles and hence release of \n 56\n\n  \nprostaglandins might explain the increased incidence of dysmenorrhoea in these women. \nPerimenopausal/postmenopausal states related hypoestrogenism is one of the explanations for \ndyspareunia in these women. \n \nWomen with CPP had higher neuroticism, anxiety and depression scores and more sexual \nproblems186 than controls, but this could be either a consequence of their pain or could \nincrease the reporting of the pain. The case-control study design makes it difficult to \ndistinguish between cause and effect. It seems the association of psychological morbidity with \nCPP could be due its link with non-organ specific pain, a conclusion supported by another\n \nmeta-analytic review of psychological factors.  19\n In recent studies, abuse has been shown to be strongly associated with depression in women \nattending general practice,187 so one might find that women who are  abused are depressed \nand hence report pain more often. Similarly, it may be worry over menstrual distress that \nleads to heightened anxiety rather than anxiety itself that prompts dysmenorrhoea. It could \nalso be that pathology, the root cause of dysmenorrhoea, may contribute to somatic imbalance \nthat is expressed in raised scores on personality inventories.188 Our review, due to the study-\nlevel nature of its analysis, is unable to disentangle these relationships. However, on the basis \nof strength and consistency of association we believe abuse and psychological morbidity to be \nat least as important as pathology for increasing the risk of CPP. \n \nProspective cohort studies would be ideal study designs for delineating relationship between \nvarious exposures and CPP. Sexual abuse victims have been shown to use dissociative \ndefenses to a greater degree189 and this increases the importance of using validated, structured \nassessment instruments while conducting future research on this group of women. As abuse \n 57\n\n \nseems to be commoner in control groups with other pain, to elicit the true association it might \nbe necessary to perform future studies with pain free controls only. The development of non-\ninvasive diagnostic tools for some of the underlying somatic conditions that may account for \nCPP will help with unraveling of some of the risk factors further. If treatment of pathology in \nCPP shows no better outcome than without treatment, then probably there is a role for trials in \npsychological interventions. It would be rational to design intervention studies of use of \npsychological counseling, antidepressants and other modifiable factors in chronic pelvic pain. \nPID has emerged as a bigger risk factor than previously realized and it seems logical to \nestablish this definitively and then explore preventative measures for CPP in women with \ndefinitive PID. One study design example is to measure chlamydia titers in women visiting \nSTD clinic, treating those with high titers and then following all these women to establish \nwhether the women who received antibiotics have reduced incidence of pelvic pain. Robust \nevidence from future aetiological studies could provide clues to experiment relevant treatment \nstrategies for millions of pelvic pain sufferers. \nKey gynaecological and psychosocial factors associated with CPP should be targeted in \nclinical evaluation of women with this symptom to individualize their management and \nachieve a satisfactory outcome. \n(PML- Pallavi Latthe; LM- Luciano Mignini; KSK- Khalid Khan) \n 58\n\n  \n \nSECTION B: SURVEY OF PRACTICE OF LAPAROSCOPIC \nUTEROSACRAL NERVE ABLATION \nIn this section, I examine the variation in current indications and surg ical techniques for \nperforming laparoscopic uterine nerve ablation  (LUNA) in Europe assess the effect of \noperator experience on practice. I also explore gy naecologists’ ‘prior’ beliefs on effectiveness \nof laparoscopic uterosacral nerve ablation (LUNA) \n \nChapter 4: Variation in practice of Laparoscopic uterosacral nerve ablation: A European \nsurvey \n \nChapter 5: Measurement of ‘prior’ beliefs about effectiveness of laparoscopic uterosacral \nnerve ablation \n 59\n\n \n \nCHAPTER 4: VARIATION IN PRACTICE OF LAPAROSCOPIC \nUTEROSACRAL NERVE ABLATION: A EUROPEAN SURVEY \n \n 60\n\n  \n4.1 ABSTRACT \nObjective  \nTo examine the variation in current indicatio ns and surgical tec hniques for performing \nlaparoscopic uterine nerve ablation (LUNA) in Europe and to assess the effect of operator \nexperience on practice. \nMethods  \nTwo groups were surveyed: I) UK gynaecologists (n=1569) and II) European Gynaecologists \n(n=301). A structured questionnai re was sent to the UK group a nd an identical email survey \nwas sent to the European group.  \nResults  \nThe questionnaire was returned by 719 (38% of  1870) of the gynaecologists contacted and \n173 (24%) performed LUNA. Indications for LUNA, which included noncyclical chronic \npelvic pain (CPP) (68%), dysmenorrhoea (66%),  dyspareunia (39%) or endometriosis (60%), \nwere similar across UK and rest of Europe. The European group performed LUNA more often \n(62% vs. 21%), completely transect the uterosac ral ligaments more frequently (56% vs. 36%) \nand more frequently ablated at a distance of more  than 2 cm from its cervical insertion (50% \nvs. 21%) than the UK group. More experience d gynaecologists performed LUNA more for \ndyspareunia (46 % vs. 26%) and endometriosis (67% vs. 47%) and they performed complete \ntransection (45% vs.26%) more often than their less experienced counterparts. \n 61\n\n \nConclusion \nThere is variation in the surgical techni ques of performing LUNA in Europe and the \ntechniques vary according to operator experience. \n 62\n\n  \n \n4.2 INTRODUCTION \nChronic pelvic pain (CPP) is frequently inve stigated by laparoscopy.  Interruption of the \nnerve pathways in the uterosacral ligaments  has been used to alleviate pain by open \nabdominal or vaginal approach in the past, 29;30 but now this procedur e can be performed less \ninvasively via laparoscopic approach. 32 Originally laparoscopic surgical experts were of the \nopinion that because of the divergence of the se nsory nerve fibres and their ganglia as they \nleave the uterus, the uterosacral ligaments s hould be vaporised as cl ose to the cervix as \npossible.32 However, recent anatomical studies have demonstrated that the greatest number of \nfibre bundles are at some distance from the site of attachment of the uterosacral ligament to \nthe cervix 33;190.  Hence there is controversy about the optimal site for laparoscopic uterosacral \nnerve ablation (LUNA). Anatomical studies also suggest that the nerve fibres are dense at a \ndepth of 3-15mm,33 thus the completeness of transection of the uterosacral ligament can also \nbe expected to have an implication for the effectiveness of LUNA.  \n \nInformation on prevalent variations in the te chniques regarding optimal site and depth of \nLUNA is currently unavailable . A previous survey showed that many UK gynaecologists \nclaimed familiarity with the operative technique of LUNA 35 but it did not explore the \ndifferences in surgical techniques with resp ect to the site and depth of LUNA. Thus I \nundertook a large survey to examine the indica tions and different su rgical techniques of \nLUNA among European gynaecologists. I was also interested in the preferences of \ngynaecologists for treating minimal-mild endometriosis in the context of LUNA.  \n \n 63\n\n \n4.3 METHODS  \nA postal survey of 1569 gynaecologists who were on the consultants’ database of the Royal \nCollege of Obstetricians and Gynaecologists (RCOG) was carried out between September- \nOctober 2002 (henceforth referred to as the UK group). I emailed the same survey to 301 \nmembers of the European Society of Gynaeco logical Endoscopy (ESGE) who were on their \nemail list (henceforth re ferred to as the European Group). I included a personalised letter to \nthe clinicians informing them of the objective of the survey. \n \nThe survey was designed to explore the differences in practice between the UK and the rest of \nEurope and between gynaecologists with varying levels of experience. To obtain information \non various issues relating to the practice of  LUNA, I included questions on indications, \nnumber of LUNA procedures performed, willingne ss to participate in a randomised trial to \nassess effectiveness of LUNA, techniques with regard to cutting modality, distance and depth \nof uterosacral ligament transection and any comp lications they had enco untered. I also asked \nthem about their routine practice of management  of minimal-mild endo metriosis encountered \nat laparoscopy.  \n \nA Microsoft Access database was used to stor e the responses. The number of procedures \nundertaken by the gynaecologist defined experi ence. Following discussion with some RCOG \ngynaecologic endoscopy preceptors, I decided to  use 20 procedures as a threshold to \ndistinguish more from less experienced gynaecologists.  \n 64\n\n  \n4.4 RESULTS \n4.4.1 Questionnaire responses \nAs shown in table 4.1, of the 1569 questionnaire s posted to the consul tants on the database \nheld by the RCOG, 661(42%) were returned. Of 301 email questionnaires sent to ESGE \nmembers, 58 (19%) were returned. The combin ed response rate was 38%. The UK group was \nthree times more likely to respond than the European group (P<0.001). Responses to \nindividual items were missing from some re spondents. In total, 146 of the 173 (85%) \nrespondents (86% and 83% in the UK and Europe respectively) who performed LUNA were \nwilling to recruit women in a randomised trial to assess effectiveness of LUNA.  \n4.4.2 Geographical variation in practice \nAs shown in table 4.1, 137/ 661 UK respondents (21%) performed LUNA in contrast to 36/58 \n(62%) of the European group (P<0.001). Indications for LUNA included chronic pelvic pain \n(68%), dysmenorrhoea (66%), dyspareunia (39%) and endometriosis (60%). The indications \nfor LUNA were similar across UK and rest of Europe as shown in table 4.2. The different \ncutting modalities were used in similar proportions across the continent as is evident from the \nresults shown in table 4. 3. As compared to 32% and 75% rates (some used both) of use for \nlaser and electrodiathermy in the UK, the rates were 36% and 78% respectively in the rest of \nEurope. Compared to the UK group, the European group performed complete transection of \nthe uterosacral ligament more often (56% vs. 36%; P = 0.05) and also transected it farther \naway from its cervical insertion more often (50% vs. 21%; P = 0.006).  \n \n \n \n \n 65\n\n \nTable 4.1: Responses to the questionnaires on practice of Laparoscopic Uterosacral \nNerve Ablation (LUNA) in the UK and the rest of Europe \n \n UK  \nn (%) \nEurope  \nn (%) \nTotal  \nn (%) \n    \nNumber of questionnaires sent 1569 301 1870 \nNumber of questionnaires received (% of Q\nsent) \n 661 (42) 58 (19) 719 (38) \nNumber that do LUNA (% of Q received) 137 (21) 36 (62) 173 (24) \nNumber Willing to Enter Patients into Trial (%\nof those who perform LUNA) \n 116 (86) 30 (83) 146 (85) \nSpeciality: Obstetrics Gynaecology \n                  Other  \n128(93) \n09 (07) \n29 (81) \n07 (19) \n157 (91) \n16(09) \nNumber of Procedures Performed in Career    \nFewer than 20 45 (33) 13 (36) 58 (32) \n20-49 60 (44) 10 (28) 70 (42) \n50-99 16 (12) 4 (11) 20 (12) \n100 or more 16 (12) 6 (17) 22 (13) \nNot stated 0 3 (8) 3(2) \n \n4.4.3 Complications of LUNA \nOf the 173 gynaecologists who performed LUNA , 169 responded to the question regarding \ncomplications with LUNA. Of these, 18 (13%) had encountered complications of LUNA; 16 \nhad come across short-term problems and 2 had seen long-term complications. The \ncommonest complication stated was bleed ing by six respondents and two respondents \nreported persistent pain. No one reported ureteric damage, prolapse or laparotomy. \n 66\n\n  \nTable 4.2 Comparison of indications for laparoscopic uterosacral nerve ablation \n(LUNA) \nIndications UK  \nN (%) \n137 \nEurope  \nN (%) \n36 \nTotal  \nN (%) \n173 \nMore  \nExperienced \n (112) \nLess \nExperienced \n(58) \n \nChronic Pelvic Pain \n \n92 (67) \n \n25 (69) \n \n117 (68) \n \n72 (64) \n \n42 (72) \nDysmenorrhoea 93 (68) 21 (58) 114 (66) 74 (66) 38 (66) \nDyspareunia 52 (38) 16 (44) 68 (39) 52 (46) 15 (26) \nEndometriosis 82 (60) 21 (58) 103 (60) 75 (67) 27 (47) \nEndometriosis: mild only 24 01 25 15 10 \nEndometriosis: mild or \nmoderate \n \n14 \n \n03 \n \n25 14 03 \nEndometriosis: moderate only 07 01 08 05 03 \nEndometriosis: moderate or \nsevere \n \n10 \n \n05 \n \n15 13 02 \nEndometriosis: severe only 08 07 15 07 07 \nEndometriosis: any severity 19 04 23 21 02 \nOther Pelvic Pain 03 (2) 01 (3) 04 (2) 04 (2) 00 \n \n4.4.4 Effect of experience on practice \nTable 4.3 compares various aspects of LUNA studied in the survey with respect to experience \nof the operating gynaecologist. Gynaecologists who had performed more than 20 LUNA \noperations used it more for dyspareunia (46% vs. 26%; P=0.01) and for endometriosis (67% \nvs. 47%; P = 0.01) than less experienced gynaecologists. They performed complete \ntransection more often (45% vs.26%; P=0.02) than their less experienced counterparts.   \n \n 67\n\n \nTable 4.3: Laparoscopic uterosacral nerve ablation (LUNA) techniques, management of \nminimal-mild endometriosis and comparison of techniques by experience \n  \n UK  \nN (%) \n137 \nEurope  \nN (%) \n36 \nTotal  \nN (%) \n173 \nMore  \nExperienced  \n112 \nLess \nExperienced \n58 \nTreatment of minimal-mild endometriosis  \nAblation with othe r\nmodality \n108 (79)  25 (69)  133 (77)  88 (79)  43 (74)  \nAblation exclusively  76 (55) 15 (42)   91 (53) 59 (53) 31 (53) \nExcision  23 (17)  15 (42)    38 (22) 27 (24)  10 (17)  \nExcision exclusively   8 (06)   5 (14)   13 (08) 10 (9)  3 (05) \nMedical treatment  39 (28)    7 (19)    46 (27)  29 (26)  16 (28)  \nMedical treatment \nexclusively \n17(12)   0   17 (10) 11 (10) 06 (10) \nCutting modality used  \nLaser 44(32)  13 (03)   57(33) 41 (37)  14 (24)  \nLaser exclusively 20 (15)  8(22)  28 (16) 21 (19)  7 (12) \nElectrodiathermy 103(75)  28 (78)  131(76)  82 (73)  46 (79)  \nElectrodiathermy \nexclusively \n62 (45) 15 (42)  77 (45) 43 (38) 32 (55) \nScissors 20 (15)   8 (22)   28 (16)  19 (17)   9 (16)  \nScissors exclusively  3 (02)  6 (17)   9 (05)  1 (01)  2 (03) \nHarmonic Scalpel  15 (11)  03 (08)   18 (10)  13 (12)   5 (09)  \nHarmonic scalpel \nexclusively \n 8 (06) 00   8 (05)  5 (04)  3 (05) \nHow uterosacral ligaments (USL) are transected \nCompletely 47 (36) 20 (56) 67 (41) 50 (45) 15 (26) \nPartially 82 (64) 16 (44) 98 (59) 58 (52) 39 (67) \nDistance from cervix for USL transection \nLess than 1cm 32 (23) 04 (11) 36 (21) 27 (24)   9 (16) \n1-2 cm 75 (55) 14 (39) 89 (51) 54 (48) 34 (59) \nMore than /= 2 cm 30 (21) 18 (50) 48 (28) 31 (28) 15 (26) \n(The responses to some items were missing or more than one and hence the figures do not add up to the total \nnumber of respondents for some questions) \n \n4.4.5 Practice in minimal-mild endometriosis \nThe approach to treatment of minimal-mild e ndometriosis encountered at laparoscopy was in \nfavour of ablation. Of the 173 respondents, 1 33 (77%) ablated endometriosis. However \n38/173 (22%) excised it and 46/173 (27%) treated it medically. Some used one or more of the \n 68\n\n  \nabove options concurrently. Compared to 108/137 (79%) of the UK gynaecologists, 25/36 \n(69%) of the other European gyn aecologists performed ablation in mild endometriosis. In the \nUK, 23/137 (17%) performed excision of which 8 respondents (6%) exclusively did only this \nfor mild endometriosis. In contrast, the compar able figures for the rest of Europe were 15/36 \n(42%) and 5/36 (14%) respectively. Among the UK group, 39/137(28%) offered medical \ntreatment and 17(12%) of these offered only this option of treatment. In the European group, \n7/36 (19%) offered medical treatment but none of them offered it exclusively without surgical \noption. \n \n4.5 DISCUSSION \nA previous survey on this topic 35 was carried out on a limited sample of members of the \nBritish Society of Gynaecological Endoscopy only. It  did not collect details of the methods of \nperforming LUNA or current methods of managi ng minimal-mild endometriosis. The current \nsurvey was designed to obtain more in-depth kn owledge of the practice across Europe. I used \na short questionnaire and prepaid envelopes. I did not have enough resources to implement \nother strategies like coloured ink for the questio nnaires, recorded first class post delivery for \nquestionnaires, reminder letters with questionnaires for non re spondents, monetary incentives \nand other such factors known to be associated with higher response191. This has a potential for \nintroduction of bias by the “responding group”. Th ere has been a trend towards reduction in \nresponse to questionnaire surveys. 192 Thus it is not surprising th at although I made all efforts \nwithin our means to enhance the return ra te, I received replies from only 38% of \ngynaecologists.193;194  \n \n 69\n\n \nThis analysis and interpretation are limited due to a differential and low response rates. This is \nalso the reason for inability to stratify the results by individual countries. The most likely \nreason for the differential responses between UK a nd the rest of Europe is the difference in \nthe types of groups surveyed. All O & G consul tants in the UK most of  who are generalists \nwere surveyed in contrast to gynaecological  endoscopists in the rest of Europe. The \ndifferences in response rates could be due to the different methods of returning the \nquestionnaires, which was by freepost in the UK wher eas it was by email, or fax in the rest of \nEurope. There are several plausible reasons for n on-response, including out of date addresses, \nlack of time in busy practice. It could also refl ect on the poor general att itude of the specialty \ntowards surgical research and evidence based practice. I observed th at the proportion of \ngynaecologists in the UK performing LUNA in this survey was 24% compared to 45% in the \nlast survey. An important difference between this survey and the previous one 35 is that the \nfirst survey was on members of the BSGE which is a more focused group with special interest \nin Endoscopy than the group in the current surv ey comprising  of all the UK consultants in \nobstetrics and gynaecology. The absolute numbers performing LUNA were 137 in the current \nsurvey versus 113 in the previous survey35 indicating that perhaps the UK consultants who are \nmembers of BSGE continue to perform LU NA while other non-member UK consultants \nrarely do so. Our finding that higher proportions  of European gynaecologists perform LUNA \nand excision of endometriosis could be due to the differences in the groups surveyed as \nalluded to before. It could also indicate different pattern of training in minimal access surgery. \nThe difference in the depth and the distance of  transection between the UK and the rest of \nEurope is difficult to explain but perhaps imp lies differences in the beliefs regarding the \nanatomy of the nerve plexuses. It  is important to emphasise the apparent safety of the LUNA \n 70\n\n  \nprocedure from the fact that none of the respondents reported uret eric damage or prolapse or \nlaparotomy to control bleeding, which have been reported anecdotally.195;196 \n  \nA high proportion of gynaecologists wish to participat e in a clinical trial to  assess the clinical \neffectiveness of LUNA. This indica tes that there is widespread c linical uncertainty in that the \ntechnique has been introduced w ithout reliable evidence of effectiveness and so the opinion \nregarding its use is uncertain and variable. There is a need for an adequately powered, \nproperly randomised trial to as sess effectiveness of LUNA, a message that has been \nhighlighted in several recent publications.39;197;198 This survey suggests that such a trial should \nalso take into consideration the impact of differing prevalent techniques for this procedure.  \n 71\n\n \nCHAPTER 5: MEASUREMENT OF ‘PRIOR’ BELIEFS ABOUT \nEFFECTIVENESS OF LAPAROSCOPIC UTEROSACRAL NERVE \nABLATION \n 72\n\n  \n5.1 ABSTRACT \nObjective  \nTo explore gynaecologists’ ‘prior’ beliefs about effectiveness of laparoscopic uterosacral \nnerve ablation (LUNA). \nMethods   \nA structured survey was used to gather information from participants on the distribution of \ntheir prior beliefs regarding the effects of LUNA on pelvic pain using a 10 point visual \nanalogue scale (VAS). ‘Prior’ beliefs were captured both graphically and textually by \nresponses to a questionnaire.  \nResults  \nNone of the 25 gynaecologists responding to the questionnaire stated that LUNA would \nincrease pain, while 2/25 gave numerical answers suggesting they believed that the \nintervention would worsen the pain. The most widely held ‘prior’ belief, reflected in both \nquestionnaire and numerical responses was that LUNA would have a small beneficial effect \non pain. The credible limits of this belief were compatible with large reductions in pain as \n60% of respondents believed a three-point improvement on VAS to be plausible. The standard \ndeviations of expected mean change in VAS due to LUNA ranged from 0.52 to 1.64.  \nConclusion \n Among gynaecologists, there is a variation in beliefs about the effects of LUNA on pelvic \npain, ranging from substantial benefit to slight harm. \n \n 73\n\n \n5.2 INTRODUCTION \nIt is ethical to initiate a clinical trial when there is collective clinical equipoise about the \neffectiveness of the available treatments.36 Prior beliefs are formed from indirect evidence \n(laboratory studies, epidemiology, extrapolation from similar treatments) and direct evidence \n(clinical trials, perhaps of an inconclusive nature). Surveys eliciting dichotomous ‘yes’ and \n‘no’ responses to a question about effectiveness are limited because clinicians’ beliefs about a \ntreatment usually amount to rather more than just “I believe it is effective” (or the converse). \nThey may believe the treatment to be greatly or marginally beneficial (or harmful). Different \nclinicians will admit varying degrees of uncertainty. Some may be rather more certain than \nthe evidence apparently warrants, others may be uncertain to a degree that they believe the \ntreatment may, in due course, turn out to be either greatly beneficial or harmful.  \n \nObserving differences in practice or, as explored here, formal measurement of beliefs about \neffectiveness can provide a clearer picture than the dichotomous responses. Formal \nmeasurements of ‘prior’ belief provide respondents with an opportunity to signal the \nmagnitude of the expected effects and the relative probabilities of effects of different sizes. \nHowever, the published examples of collecting such information are sparse, in both obstetrics \nand gynaecology and in medicine.\n199 \n \nA recent survey has indicated that there is wide variation in the practice and use of \nlaparoscopic uterosacral nerve ablation (LUNA) for treatment of chronic pelvic pain among \nclinicians, suggesting that collective clinical equipoise is present. The technique has been \nintroduced without definite evidence but opinion regarding its use has not yet solidified, as \n81% of gynaecologists performing LUNA stated their willingness to recruit patients in a trial \n 74\n\n  \nto assess effectiveness of LUNA.35 However, this survey does not provide information on \ndistribution of beliefs concerning effectiveness of LUNA in alleviating pelvic pain. Therefore \na structured survey to formally document the range of beliefs on effectiveness of this surgical \ntreatment was undertaken.  \nIn this chapter, I illu strate a method of collect ing ‘prior’ beliefs of c linicians about possible \neffectiveness of an intervention. \n \n5.3 METHODS  \nA survey was administered with oral explanation to a ‘captive’ group of participants in a \nCollaborators’ meeting of the LUNA trial200 in November 2002. The survey questionnaire is \nprovided in the appendix. The aim was to obtain distribution of their beliefs about the likely \neffectiveness of LUNA in alleviating pelvic pain, compared to placebo i.e. laparoscopy alone. \nAn example of how the survey of beliefs was explained is as follows: Suppose a clinician is \nasked to predict what the true benefit of LUNA is likely to be in reducing pain in suitable \npatients. Pain is to be measured using a Visual Analogue Scale (VAS) from 0 to 10, with 0 \nindicating no pain and 10 indicating greatest conceivable pain. The outcome to be predicted is \nthe mean extra change (before - after) in VAS scores in patients receiving LUNA, compared \nto the mean change in patients receiving placebo treatment i.e. laparoscopy alone. Thus, if the \ntrue mean change in VAS score in patients treated with LUNA is a reduction of 1.3 in pain \nscore, while the true mean change in similar patients treated with placebo is an increase of \n0.2, then the true benefit from LUNA would be 1.5. On this scale, it is arbitrarily decided that \nthe improvement of 0.5 to 1.5 points would be a small benefit, an improvement of 1.5 to 2.5 \npoints to be a moderate benefit, and an improvement of 2.5 points or more to be a substantial \nbenefit.  \n 75\n\n \n \nFigure 5.1: A sample of a graphical elicitation of beliefs about the likely true effect of \nlaparoscopic uterosacral nerve ablation (LUNA) compared to placebo (laparoscopy \nalone), in patients with chronic pelvic pain, as measured by change in 10-point visual analogue scale (VAS) \nscores (see text for details). This approach provided numerical estimation of ‘prior’ beliefs. \nTrue mean effect of LUNA\nIncreasingly likelyImpossible\n(Placebo substantially better) -2.5\n(Placebo moderately better) -2.0\n(Placebo moderately better) -1.5\n(Placebo slightly better)  -1.0\n(Placebo slightly better)  -0.5\n(No benefit over placebo)\n(LUNA slightly better)  +0.5\n(LUNA slightly better)  +1.0\n(LUNA moderately better) +1.5\n(LUNA moderately better) +2.0\n(LUNA substantially better) +2.5\n(LUNA substantially better) +3.0\nSubjective probability of effect\n \nFigure 5.1 provides an example of how the plots of beliefs were drawn. The participants were \nbriefed on filling the numeric scale as follows:  If the participant believes that the most likely \nbenefit from LUNA in suitable patients is (on average) zero (i.e. negligible benefit or harm), \nthen he/she should first mark the zero benefit line somewhere towards the right of the page. If \nhe/she believes that a mean 1.5 point or more disadvantage (i.e. LUNA moderately worse \ncompared to placebo) is extremely unlikely, she should mark the –1.5 and –2.0 lines at or very \nclose to the left end. Similarly, if he/she believes a mean benefit of 3.0 points or more (i.e. \nLUNA substantially better compared to placebo) is extremely unlikely, he/ she would mark \nthe last line at the left-hand end. He/she then needs to consider how much less likely than zero \n 76\n\n  \nare mean changes of –0.5 and +0.5 are. Suppose he/she thinks +0.5 (i.e. a small benefit) is \nabout half as likely, while –0.5 (i.e. a small harm) is about a quarter as likely, then he/she \nshould mark these lines accordingly. All of the above details were briefly explained by a short \npresentation in the meeting. This procedure produced a distribution that represents the \nrespondent’s beliefs - a “Bayesian prior”. \n \nWe also asked the participants to describe their beliefs on the true mean effect of LUNA on \npain, compared to standard treatment, by selecting a response from a number of statements or \nwriting their own statement of beliefs. The graphical representations of the beliefs were \n‘triangulated’ with the textual statements to assess their compatibility. We used the \nrespondent’s chosen statement describing their beliefs as a way of checking whether an \nelicited graphical representation really could be said to represent the respondent’s beliefs. To \nthis end, three assessors (see acknowledgement) independently assessed the compatibility of \ntextual statement and graphical representation for each respondent. The responses were \nprocessed and analysed using a spreadsheet. The mean weighted change in VAS was \ncalculated for each respondent by multiplying the VAS with its likelihood (distance from left \nend in cm) and then taking average of all the values obtained. \n \n5.4 RESULTS \nThe survey was distributed to 30 gynaecologists of whom 25 responded. Their distribution of \nthe beliefs on basis of the textual responses is given in table 5.1. The distribution of numerical \n‘prior’ beliefs by graphical re presentation is summarised in figure 5.2. The range of means \nwas –0.40 to 1.81. The standard deviations of e xpected mean change in VAS due to LUNA \nranged from 0.52 to 1.64.  \n 77\n\n \n 78\nTable 5.1: Clinicians’ textual ‘priors’ beliefs on the effect of laparoscopic uterosacral \nnerve ablation (LUNA) on pain \nResponse Number of clinicians \n(N=25) \nHarmful or no benefit 0 \nNegligible benefit or harm (near 0 on VAS) 5 \nSlightly beneficial (0.5 to1.5 reduction) 12 \nModerately beneficial (1.51-2.5 reduction) 4 \nSubstantially beneficial (2.5 or more reduction) 2 \nBeneficial but unsure how much 0 \nUnsure whether beneficial or not, but not \nharmful (0 or more reduction) \n1 \nUnsure whether harmful or beneficial 1 \nOther (own description if none fits well) 0 \n \n\n \n \n \n79\nFigure 5.2: Graphical representation of numerical ‘prior’ \nbeliefs\n \nDoctor 1\n0\n0.25\n0.5\n0.75\n3 - 2- 10 12 3\nDoctor 2\n0\n0.25\n0.5\n0.75\n3 - 2 - 10123\nDoctor 3\n0\n0.25\n0.5\n0.75\n3- 2- 10 1 2 3\nDoctor 6\n0\n0.25\n0.5\n0.75\n3 - 2- 1 0 123\nDoctor 5\n0\n0.25\n0.5\n0.75\n3- 2- 10 1 2 3\nDoctor 4\n0\n0.25\n0.5\n0.75\n3- 2- 1 0 1 2 3\nDoctor 7\n0\n0.25\n0.5\n0.75\n3- 2 - 10 12 3\nDoctor 8\n0\n0.25\n0.5\n0.75\n3- 2- 10 12 3\nDoctor 9\n0\n0.25\n0.5\n0.75\n3- 2 - 1 0123\nDoctor 10\n0\n0.25\n0.5\n0.75\n3- 2 - 10123\nDoctor 16\n0\n0.25\n0.5\n0.75\n3 - 2- 1 0 123\nDoctor 12\n0\n0.25\n0.5\n0.75\n3- 2 - 10 12 3\nDoctor 13\n0\n0.25\n0.5\n0.75\n3- 2- 10 1 2 3\nDoctor 14\n0\n0.25\n0.5\n0.75\n3- 2- 10 12 3Size of Benefit\nSubjectiv\ne \nDoctor 14\n0\n0.25\n0.5\n0.75\n3- 2- 10 1 2 3\nDoctor 15\n0\n0.25\n0.5\n0.75\n3- 2 - 10 12 3\nDoctor 11\n0\n0.25\n0.5\n0.75\n3- 2 - 10 12 3\nDoctor 17\n0\n0.25\n0.5\n0.75\n3- 2 - 10 12 3\nDoctor 18\n0\n0.25\n0.5\n0.75\n3- 2- 10 12 3\nDoctor 19\n0\n0.25\n0.5\n0.75\n3- 2 - 10 12 3\nDoctor 20\n0\n0.25\n0.5\n0.75\n3- 2 - 10 12 3\nDoctor 21\n0\n0.25\n0.5\n0.75\n3 - 2- 1 0 123\nDoctor 22\n0\n0.25\n0.5\n0.75\n3- 2- 10 12 3\nDoctor 23\n0\n0.25\n0.5\n0.75\n3- 2- 10 12 3\nDoctor 24\n0\n0.25\n0.5\n0.75\n3- 2 - 10 1 2 3\nDoctor 25\n0\n0.25\n0.5\n0.75\n3- 2 - 10 1 2 3\nSubjective Probability\nSize of Benefit\n\n  \n \nThe graphical representations of the beliefs when ‘triangulated’ with the textual statements as \nshown in figure 5.3, showed reasonable compatibility in that none were judged to be totally \nincompatible by any of the three assessors.  \nThe observed difference in mean change in VAS between the ‘compatible’ and ‘some \nincompatibility’ group was 0.27. The mean changes in VAS in both groups, however, is less \nthan 2 points change on the VAS, which is the minimal clinically relevant difference assumed \nin the LUNA trial. The following results pertain to those respondents judged compatible on \nnumeric and textual descriptions by all three assessors (10/25): expected mean change in VAS \nranged from a small (0.1 points) increase to a substantial decrease (1.8 points).  The expected \nmean change in VAS due to LUNA on the numerical representation was 0.8 points reduction. \nThe most pessimistic of these respondents predicted a mean change of 0.1 increase while the \nmost optimistic respondent predicted a mean change of 1.8 point reduction in VAS scores. In \nresponses where some incompatibility (15/25) between graphical and textual representation \nwas observed (7/25 were thought to be compatible by two of the three assessors), the mean \nbenefit was slightly less at a 0.51 point decrease on VAS. The observed difference in the \nmean change in VAS between the groups was 0.27 (confidence interval –0.17 to 0.72) with \nthe ‘compatible’ group being more optimistic of the benefits of LUNA than the incompatible \ngroup, but this could simply be due to chance (P = 0.21).  \nFigure5. 3 shows the correlation of textual and graphical beliefs with regards to the effects of \nLUNA. \n 80\n\n  \nFigure 5. 3: Agreement between graphical and textual representation of beliefs of effects of \nlaparoscopic uterosacral nerve ablation (LUNA) \n-0.5\n0\n0.5\n1\n1.5\n2\n01 0 2 0 3 0\nTextual belief\nGraphical belief\nmean weighted\nchanges in VAS\n \n5.5 DISCUSSION \nThere is variation in beliefs on the effectiveness of LUNA in pelvic pain, ranging from \nsubstantial benefit to slight harm. This study represents one of the very few attempts at formal \ncollection of ‘prior’ beliefs from participants in a randomised controlled trial and possibly the \nfirst in gynaecological surgery. There might have been more variation if the sample surveyed \nwas more representative of the general clinical opinion. The majority of respondents felt that \nLUNA would benefit the patient in terms of change in VAS but there was wide variation in \nthe expected level of benefit. The clinicians did not agree about the benefits of LUNA and \nthere was collective and reasonably balanced uncertainty201 - the main requirement for a \nrandomised trial.36 The measurement of prior beliefs can be used for calculation of sample \nsizes as well as in Bayesian analysis of clinical trials.202;203 A double blind randomised \ncontrolled trial to assess effectiveness of LUNA is currently recruiting women with pelvic \npain in the UK.200 We will be able to update these beliefs when the LUNA trial results are \navailable and see whether clinicians’ beliefs change in line with Bayesian formulae. \n \n 81\n\n  \nThe elicitation process used in the study was designed to be quickly self-completed with a \nminimum of exploration. The use of a textual statement to ‘triangulate’ with graphical priors \nis, a useful avenue to pursue, but one that is in need of further work. About half of elicited \n‘priors’ were unanimously agreed to be compatible with the textual statements. This \nperformance may be in part due to remediable problems with the elicitation process, but it \nmay point to a more fundamental truth - that for many respondents, substantial effort (from \nresearcher and respondent) may be required before a valid prior can be elicited. The effort \nmay include any or all of the following: re-examination of the evidence, extensive exploration \nof the task, feedback of the implications of elicited priors with the opportunity for revisions, \ndiscussion with colleagues etc. It would also have been useful to know at what expected level \nof benefit would the clinicians be inclined to offer LUNA to their patients.  \n \nMethods of documenting distribution of beliefs about likely effects of a treatment need further \ndevelopment.204;205 Our survey is one such step in this direction. It would also be interesting \nfor methodological researchers to compare the graphical and textual methods of collecting \n“Bayesian priors” and explore the factors that potentially will lead to better representation of \nthe clinicians’ opinions.  \n \n 82\n\n  \nSECTION C: EVIDENCE ON EFFECTIVENESS OF LUNA AND LUNA \nTRIAL PROTOCOL \n \nIn this section I have endeavored to determine the effectiveness of neuroablation in CPP by \nmeans of a Cochrane systematic review and develop a protocol for a prospective randomised \ncontrolled trial to assess the effectiveness of LUNA in CPP  \n 83\n\n  \n \nCHAPTER 6: EFFECTIVENESS OF NEUROABLATION IN \nRELIEVING CHRONIC PELVIC PAIN (DYSMENORRHOEA): \nUPDATE OF COCHRANE SYSTEMATIC REVIEW \n 84\n\n  \n6.1 ABSTRACT \nObjective \nTo assess the effectiveness of surgical interrupt ion of pelvic nerve pathways as treatment for \nchronic primary and secondary dysmenorrhoea. \nMethods \nThe Cochrane Menstrual Disorders and Subfertil ity Group trials register (searched 9 June \n2004), CENTRAL (The Cochrane Library Issue 2, 2004), MEDLIN E (1966 to Nov 2003), \nEMBASE (1980 to Nov 2003), and CINAHL (1982 to Oct 2003) were searched. Attempts \nwere also made to identify trials from the meta Register of Controlled Trials and the citation \nlists of review articles and included trials . The inclusion criteria were randomised \ncomparisons of surgical techniques of interr uption of the pelvic nerve pathways (both open \nand laparoscopic procedures) for the treatment of primary and secondary dysmenorrhoea. The \nmain outcome measures were pain relief and adverse effects. The data was pooled in meta-\nanalysis to obtain Peto odds ratios with 95% confidence intervals.  \nResults \nNine RCTs were included in the systematic review. There were two trials with open presacral \nneurectomy (PSN); all other trials used laparoscopic techniques. For the treatment of primary \ndysmenorrhoea, laparoscopic uterosacral nerve ablation (LUNA) at 12 months was better \nwhen compared to a control or no treatment (Odds Ratio or OR 6.12; 95% confidence interval \n/CI 1.78-21.03). The comparison of LUNA with PSN for primary dysmenorrhoea showed that \nat 12 months follow up, PSN was more effective (OR 0.10; 95% CI 0.03-0.32). In secondary \ndysmenorrhoea, along with laparoscopic surgical treatment of endometriosis, the addition of \n 85\n\n  \nLUNA did not improve the pain relief (OR 0.77; 95% CI 0.43-1.39) while PSN did (OR 3.14; \n95% CI 1.59-6.21). Adverse events were more common for PSN than procedures without \nPSN (OR 14.6; 95% CI 5-42.5). \nConclusion \nThe evidence to recommend the use of nerv e interruption in the management of \ndysmenorrhoea, regardless of cause, is stil l insufficient. Methodologically sound and \nsufficiently powered RCTs should be undertaken in future. \n 86\n\n  \n \n6.2 INTRODUCTION \nDysmenorrhoea is a very common gynaecological  complaint that can affect up to 50% of \nwomen. Although the use of  both OCPs and NSAIDS 206;207 has been very successful, there is \nstill a 20 to 25% failure rate.21;208 Surgery has been a treatment for cases of dysmenorrhoea that \nfail to respond to medical therapy. When di agnostic laparoscopy is indicated, laparoscopic \nuterine nerve ablation (LUNA) and presacral neurectomy (PSN) are two surgical treatments \nthat have become increasingly utilised in recen t years and as described in chapter 1 (section \n1.4), both interrupt the majority of  the cervical sensory nerve fi bres, thus diminishing uterine \npain.32 Observational studies have supported the use of LUNA for both primary and secondary \ndysmenorrhoea with either complete relief or substantial reduction in menstrual pain in the \nmajority of subjects. 209-215 PSN involves the interruption of a greater number of nerve \npathways than LUNA, therefore it is a more complex procedure than LUNA, and entails more \noperative risk. 216 However, despite these drawbacks the use of PSN is also supported by \nobservational studies showing sim ilar results to that of LUNA for both primary and secondary \ndysmenorrhoea. 217;218 \n \nIn order to determine the effectiveness of surgi cal interruption of pelvic nerve pathways (both \nopen and laparoscopic UNA or PSN), I compar ed UNA/PSN to no treatment (where the \ncontrol group is either no trea tment or a recognised treatment wh ich is also performed in the \nintervention group) and also explored if the effects vari ed according to: 1) primary or \nsecondary dysmenorrhoea and 2) UNA or PSN. \n \n 87\n\n  \n6.3 METHODS \nA protocol for updating Cochrane reviews was adopted.219 \n6.3.1 Data sources \nAll reports that described (or might describe ) randomised controlled trials of surgical \ninterruption of pelvic nerve pathways (both open and laparo scopic) in the treatment of \ndysmenorrhoea were obtained using the search strategy developed by the Menstrual Disorders \nand Subfertility Group. Following were searched: \n(1) The Cochrane Menstrual Disorders and Subfertility Group trials register (searched 9 June \n2004). \n(2) The Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, \nIssue 2, 2004. \n(3) The electronic databases MEDLINE (1966 to April 2004), EMBASE (1980 to April 2004), \nand CINAHL (1982 to April 2004) using OVID software. \n(4) The metaRegister of Controlled Trials. \n(5) Citation lists of review articles and all included and excluded trials.  \n In most cases, the first or corresponding au thors of included trials were contacted for \nadditional information. The following keywords we re used to search the above databases: \ndysmenorrhea, dysmenorrhoea, painful menstruation, pelvic pain/surgery/, laparoscopy, \nsurgical procedures, laparoscopic denervation, uterine nerve ablation, presacral neurectomy.  \n \n6.3.2 Study selection \nAll prospective randomised controlled trials comparing surgical interruption of pelvic nerve \npathways (both open and laparoscopic UNA and PSN ) to no treatment, or other treatment, for \n 88\n\n  \nwomen with primary or secondary dysmenorr hoea were considered. Two reviewers (MP and \nPL) performed the selection of trials for inclusion after employing the search strategy described \nabove. These trials included women of reproductive years with primary dysmenorrhoea (no \nidentifiable organic pathology) or secondary dysmenorrhoea (identifiable specific pathology). \nLaparoscopic and open techniques are combined for these interventions, as there is some \nevidence to suggest they have similar ranges of pain relief for dysmenorrhoea. 211;217 The \noutcome measures we looked at were: (1) Pain relief after treat ment (at 6 months and more): \nMeasurement with the VAS or other validated pain scales were studied and where these are not \nused other scales or dichotomous data as we ll as changes in pain intensity were also \nconsidered. (2) Adverse effects from the treatment (dichotomous data, number of participants \nwith side effects) (3) Quality of life \n \n6.3.3 Quality assessment of included trials \nAll assessments of the quality of trials and da ta extraction were performed independently by \nthe two reviewers (MP and PL) using forms designed according to Cochrane guidelines. A \nthird reviewer (NJ) resolved any discrepancies. Additional inform ation on trial methodology \nand/or actual original tr ial data was sought from the authors of trials which ap peared to meet \nthe eligibility criteria but had aspects of methodology that were unclear, or where the data were \nin a form unsuitable for meta-analysis.  \n \nWe assessed the trials for the following quality criteria: method of randomisation, quality of \nallocation concealment until randomisation, pres ence or absence of blinding to treatment \nallocation after randomisation, explicit statem ent about the number of women randomised, \n 89\n\n  \nexcluded or lost to follow up, whether an inte ntion to treat analysis was done and whether a \npower calculation was done. \n \n6.3.4 Data synthesis \nAttempts were made to dichotomise the pain relief data in order to  do sub-group analyses. \nOther pain scales were collapsed into dichotomou s outcomes, pain relief or no pain relief. For \nexample. if pain relief was measured on a scale of 0 (no pain)-5  (maximum pain imaginable), \n0-2 was considered as pain relief. 11 \n \nStatistical analyses were to be performed according to the statistical guidelines for reviewers in \nthe Menstrual Disorders and Subfertility Review Group.220 For the dichotomous data, results of \neach study were expressed as an odds ratio wi th 95% confidence intervals and combined for \nmeta-analysis with RevMan software using the Peto-modified Mantel-Haenszel method. The \noutcome of pain relief is considered a positive consequence of treatment therefore a higher \nproportion of women with pain relief is consider ed a benefit (OR>1), wh ereas the outcome of \nadverse effects is a negative consequence ther efore higher numbers are considered to be \ndetrimental (OR <1). This needs to be taken in to consideration when the summary graphs are \nviewed. \n \n6.4 RESULTS \n6.4.1 Literature identification, selection and characteristics  \nA total of 288 articles were id entified. Ten RCTs involving surgic al interruption of the pelvic \nnerve pathways as treatment for dysmenorrhoea were selected. Out of these, one trial was \n 90\n\n  \nexcluded from the review. The excluded trial 221 compared laser laparoscopy (involving LUNA \nand surgical treatment of endometrial implants ) to no treatment (expectant management only). \nTherefore due to the lack of a control group th at had laser vaporisation only, the outcome data \nas a result of LUNA surgery could not be di stinguished from the outcomes resulting from the \nlaser vaporisation. \n \nNine RCTs met the criteria for inclusion in the review. All the studies described clear inclusion \nand exclusion criteria (see append ix Table 7.1 of characteristic s of included studies). All the \ntrials included women between the ages of 18 to 50 years of age, and the majority of the \nstudies' participants appear to have sought medi cal assistance for dysmenorrhoea. None of the \ntrials gave clear information on the source of th eir women or how they were recruited into the \nstudies. Two of the studies 11;222 looked exclusively at women with primary dysmenorrhoea, \nexcluding all participants with any pelvic pathology usi ng a diagnostic laparoscopy. One study \nincluded women with dysmenorrho ea related to uterine myoma. 223 One study included two \npatient groups, women with primary dysmenorrhoea and women with secondary \ndysmenorrhoea associated with endometriosis. 224 The other studies included women with \nsecondary dysmenorrhoea associated with endometriosis. Two of the included studies involved \nwomen with endometriosis included those with  an AFS classificatio n of stage III - IV \nendometriosis 225;226 one trial included women with only stage I – III, 227 and the other trials \nincluded all stages I – IV. 224;228;229 \n \nTwo trials11;224 compared laparoscopic uterine nerve ablation with diagnostic laparoscopy only, \nfor women with primary dys menorrhoea. Three trials 224;227;228 combined LUNA and laser \ntreatment of endometriosis impl ants as surgical techniques a nd compared them with laser \n 91\n\n  \ntreatment only, for women with secondary dysmenorrhoea. One trial compared LUNA and \nlaparoscopic bipolar coagulation of uterine vess els with laparoscopic bi polar coagulation of \nuterine vessels only in women with dysmenorrhoea secondary to uterine myomas. 223 Three \ntrials compared presacral neurectomy combined with surgical treatm ent of endometriosis \nversus surgical treatment of endometriosis only as a control for treatment of secondary \ndysmenorrhoea. 225;226;229 The final included trial compared LUNA and LPSN as treatments for \nprimary dysmenorrhoea. 222  \n \nThe primary outcome in all trials was pain relief. This was measured and reported in a variety \nof ways. Two studies used a 5-point pain scale.11;222 VAS were also used in some of the trials, \nhowever the length of the scales varied. One trial used a 10cm VAS as well as a 10-point pain \nscale.227 One study used a 10 point VAS (but only reported dichotomised data) and a \nmultidimensional scale. This scale comprised 3 components: limitation of working ability, \ncoexistence of systematic symptoms and need for analgesics.225 One study used a 100mm \nVAS230, and another simply reported whether pain relief did or did not occur. 226 The majority \nof studies also reported side effects; these were reported as the number of women who suffered \nany specific adverse events for example constipation.  \n \nOutcomes were assessed at various time periods following surgery. In two trials 223;226, \nparticipants were assessed at 6 months, although one trial226 stated that participants were \nfollowed for a minimum of 42 months. One trial assessed participants at 3 and 6 months.227 In \ntwo trials 222;224 participants were assessed at 3 and 12 months. Two trials228;229 assessed \nparticipants at 6 and 12 months, although one of this228 extended follow up of some women for \n 92\n\n  \nup to 36 months. In the final two trials 11;225 all participants were followed up for at least 12 \nmonths.  \n \nFigure 6.1: Study selection process for systematic review of neuroablation in \ndysmenorrhoea (LUNA- laparoscopic uterosacral nerve ablation; PSN- presacral neurectomy) \nTotal citations identified from electronic searches to \ncapture articles (n= 260)\nCitations excluded after \nscreening titles and/ or \nabstracts (n=226)\nArticles retrieved for detailed evaluation from \nelectronic search (n=34)\nHand searches (n=0)\nPSN vs. LUNA (n=1)\nPapers excluded: 23\nDuplicate data or follow-up report 3\nComment/letter/discussion/ case-control \nstudy/case report/ review  20\nPSN vs. control (n=3) LUNA vs. control (n=5)\nPotential studies identified \n(n=11)\nStudies excluded due to inappropriate \ncontrol group or population (n=2)\n \n6.4.2 Methodological quality of included studies \nAll the included studies assessed comparability of the treatment and control groups at baseline, \nno appreciable differences in age, parity, condition or pain scores were reported. \nFive of the trials had adequate  concealment prior to allocation. 224;226-229 Two studies had \ninadequate concealment, 11;223 due to the use of case numbers in the allocation process. Double \nblinding was used in six studies with bli nding of the patient and the investigator, 11;223;224;227-229 \none was single blind, 226 and for the other trials blinding was unclear. Two trials 224;228 included \nan intention to treat analysis. A power calculation was performed in five studies. 224;225;227-229 In \n 93\n\n  \none study, although the power calculation was done, the trial was stopped before the number of \nwomen needed was reached. 226  \n \nFigure 6.2: Methodological quality of studies included in the systematic review of effectiveness of \nneuroablation in dysmenorrhoea (data presented as 100% stacked bars; figures in the stacks represent \nnumber of studies). \n7\n5\n2\n6\n3\n2\n4\n7\n3\n6\n0% 10% 20%30% 40% 50% 60% 70%80% 90%100%\nFollow up > 85%\nSample size estimation\nIntention to treat\nanalyses\nDouble blinding\nConcealment\nadequate/yes\ninadequate/no\n \nFollow up and withdrawal rates varied among trials. Two trials  reported no withdrawals or \nlosses to follow up. 222;226 In four trials less than 15% of randomised participants withdrew or \nwere lost-to-follow up. 223;225;227;229 In one trial of 180 participants only 116 were analysed; 29 \nbecame pregnant, 14 used OCP, 15 (8%) were lost-to-follow up, six women withdrew for other \nreasons. 228 In another trial of 18/39 women (46%) were excluded from analysis due to \npathology at follow up. 11 \nThere were two trials with open PSN and none of open uterosacral nerve ablation. \n 94\n\n  \n6.4.3 Effectiveness of neuroablation \n6.4.3.1 LUNA versus control  \nThere were two studies comparing LUNA versus control for primary dysmenorrhoea.11;224 At 6 \nmonths or less follow up there was no significant difference in pain relief (2 RCTs; n = 68; OR \n1.43, 95% CI 0.56 to 3.69). However longer-term pain relief (assessed at 12 months) showed a \nsignificant difference between the experimental and control groups (2 RCTs; n = 68; OR 6.12, \n95% CI 1.78 to 21.03). \n \nOne trial 224 reported additional outcomes related to quality of life following treatment. \nSatisfaction rates at 12 months showed no difference between the groups (LUNA 15/18 vs. \ncontrol 22/32; p>0.05). Information on the need for further surgery (one hysterectomy in the \nLUNA group and 2 in the control group), and the need for additional treatment (3 women in \nthe no LUNA group were using OCP or Mirena), also indicated no difference between the two \ngroups.  \nThere were three trials that compared LUNA w ith surgical treatment of endometriosis versus \nsurgical treatment of endometriosis only. 224;227;228 At 6 months or less follow up there was no \nsignificant difference in pain relief (3 RCT s; n = 190; OR 1.03, 95% CI 0.52 to 2.02). Longer-\nterm pain relief also showed no significant difference between groups (2 RCTs; n = 217; OR \n0.77, 95% CI 0.43 to 1.39). \n \n One trial 227reported comparable baseli ne pain scores, and at six months post-operative \nshowed no significant difference between the experimental and control groups for \ndysmenorrhoea pain scores on the VAS scale (M ann-Whitney test, p=0.21). On the 10cm VAS \n 95\n\n  \nscale the experimental group pain scores at 6 months had a median of 4.8 (range 1-9.0), while \nthe control pain scores had a median of 3.0 (range 0-9.8).  \nAnother trial found  no significant difference in pain relief between the treatment and control \ngroup following extended follow up of up to 36 months (1 RCT; n=116; OR 0.84, 95% CI 0.39 \nto 1.80)228. The 12-month Kaplan-Meyer cumulative probability of recurrence of moderate to \nsevere dysmenorrhoea was 33.7% for the experimental group and 27.55% for the control \ngroup. An intention to treat analysis on subject satisfaction showed that 68% of the \nexperimental group and 73% of the control group were very satisfied or satisfied with \ntreatment, while 32% of the experimental group and 27% of the control group were uncertain, \ndissatisfied, or very dissatisfied with treatment. No adverse effects were reported for either \ngroup. In this trial, additional quality of life data was collected. There were significant mean \nimprovements in all scales; however at one year follow up the trial reported that there were no \nsignificant differences between groups.  \n \n6.4.3.2 PSN versus control \nThree trials compared PSN with surgical treatment of endometriosis versus surgical treatment \nof endometriosis only.225;226;229 At 6 months (or less) follow up there was no significant \ndifference in pain relief (1 RCT; n = 126; OR 1.23, 95% CI 0.50 to 3.00). Pain relief measured \nup to 12 months following treatment also showed no significant difference between treatment \ngroups (2 RCTs; n = 197; OR 1.38, 95% 0.67 to 2.83). However in one trial, the authors \noriginally collected information on the incidence, site and severity of pain and in analysis split \ntheir results into separate areas of pain.\n225 They interpreted their findings as showing a \nsignificant difference in the recurrence of midline abdominal dysmenorrhoea, with the \n 96\n\n  \nexperimental group reporting what the authors interpreted as a significantly lower recurrence \n(p=0.06). There was a strong significant difference in the proportion of women with adverse \neffects from the treatment; the control group reported none but the PSN group reporting 13 \nwomen with constipation, 3 with urinary urgency and 2 experienced a painless first stage of \nlabour (OR 14.6, 95% CI 5.0 to 42.2). This trial also evaluated dysmenorrhoea on a \nmultidimensional scoring system that included limitation of working ability, systemic \nsymptoms, and need for analgesics. There was no significant difference between the treatment \nand control groups with both group showed a large reduction in symptoms (absent or mild \nsymptoms - PSN 30/35 women, control 29/36 women). In another trial, where information on \nlocation of pain was collected, it was found that the experimental and control groups were \nsignificantly different in pain relief for midline abdominal pain (Fisher exact test, p= .028). \nHowever for back pain or lateral pain associated with dysmenorrhoea there were no significant \ndifferences between the groups. These results are based on only the eight randomised \nparticipants\n226.  \n \nFigure 6.4: Results of metanalyses of effectiveness of neuroablation in dysmenorrhoea \n(LUNA- laparoscopic uterosacral nerve ablation, PSN- presacral neurectomy; shaded diamonds= statistically \nsignificant result; safety*: OR<1= LUNA is safer than LPSN and OR>1 = PSN has more adverse effects than \ncontrol/no PSN)  \n 97\n\n  \nOdds ratios\n(95% confidence interval)\n1 804020\nLUNA vs. PSN*\nLUNA vs. LPSN (1 study, 68 women) \nLUNA vs. LPSN (1 study, 68 women)\nPSN vs. control (2 studies, 197 women)\nPSN vs. control (1 study, 126 women) \nLUNA vs.control (1 study, 116 women)\nLUNA vs. control (2studies, 217 women)\nLUNA vs. control (2 studies, 68 women)\nFollow-up 12 months\nLUNA vs. control (3 studies, 190 women)\nLUNA vs. control (2 studies, 68 women) 1.43 (0.56, 3.69)\n0.67 (0.17, 2.61)\n0.10 (0.03, 0.32)\n14.57 (5.04, 42.5)\n0.02 (0.01, 0.06)\n1.03 (0.52, 2.02)\n0.77 (0.43, 1.39)\n0.84 (0.39, 1.8)\nPSN vs. Control* \n3.14 (1.59, 6.21)\n4.52 (1.84, 11.09)\n6.12 (1.78, 21.03)\nFavours LUNA or PSNFavours Control or LPSN\nEffectiveness in Primary dysmenorrhea\nFollow-up 6 months\nEffectiveness in Secondary dysmenorrhea\nFollow-up 6 months\nFollow-up 12 months\nFollow-up 36 months\nSafety*\n \n6.5 DISCUSSION  \nThis review assessed the effectiveness of surgical  interruption of pelvic nerve pathways in the \ntreatment of dysmenorrhoea. There is insuffici ent evidence to recommend the use of nerve \ninterruption in the management of dysmenorrhoea, regardless of  cause. Adverse events were \nsignificantly more common fo r presacral neurectomy, how ever the majority were \ncomplications such as constipation, which may spontaneously improve.  \n \nThe systematic review was rigorously carried out with an extensive and rigorous literature \nsearch without foreign language restrictions an d with formal assessment of study quality to \nevaluate bias. It met most of the quality criteria laid down in the QUOROM statement (see \nappendix 6.2).23 The review has been done adhering to a strict protocol.  \n 98\n\n  \nDue to a small number of participants and predictable allocation of randomisation the results \nshould be treated with caution. In the evaluation of the effectiveness of LUNA in treating \nsecondary dysmenorrhoea a meta-analysis of the data is to be viewed with caution due to the \nrelevant studies being heterogeneous in the baseline characteristics and stages of \nendometriosis. Quality of life measures were reported in only one study225 though \nimprovement of this is the ultimate goal for the patient and the clinician. Overall the small \nnumber of participants who have been entered into randomised controlled trials on LUNA and \nPSN make it difficult to assess effectiveness in treating dysmenorrhoea. In the trials with \nnegative results, inadequacy of power to detect a clinically important difference is an issue of \nconcern. Overestimation of the expected clinical difference at the time of power calculation \ncan lead to underestimation of the sample size, with the observed effect size showing wide \nconfidence intervals indicating a potential for benefit as well as harm at the extremes of the \nconfidence intervals. The other drawbacks of the included studies are single (fixed) block \nrandomisation, lack of intention to treat analysis and limited generalisability of results due to a \nsingle centre trial.  \n \nLaparoscopic PSN is a surgical procedure that requires a high degree of skill by an experienced \npelvic laparoscopic surgeon trained specifically in  this retroperitoneal operation. The presacral \nregion may be highly vascular and the procedure carries major potential hazards for the unwary \nor inadequately trained surgeon. Conversely,  although laparoscopic UNA must be performed \nprecisely to avoid complications it should be within the scope of all competent pelvic \nlaparoscopic surgeons. Not withstanding this fact, there is insufficient evidence to recommend \nthe use of nerve interruption in the mana gement of dysmenorrhoea and data from \nmethodologically sound trials must be awaited before changing current practice. \n 99\n\n  \n \nThere is a lack of good quality RCTs in all the comparisons examined in this review. The main \nissues are sample size and trial methodology. To help resolve the issue of effectiveness of \nneuroablation, clinicians may initiate good quality and adequately powered trials or participate \nin the ongoing multicentre trials. An individual patient data metanalysis may address the \nuncertainty by combining raw data from various st udies included in this review as well as the \ndata from ongoing studies.231 \n 100\n\n  \n \nCHAPTER 7: A RANDOMISED CONTROLLED TRIAL TO ASSESS \nTHE EFFECTIVENESS OF LAPAROSCOPIC UTEROSACRAL NERVE \nABLATION (LUNA) IN CHRONIC PELVIC PAIN: THE TRIAL \nPROTOCOL \n 101\n\n  \n7.1 ABSTRACT \nObjectives \nThe principal objective of the trial is to test the hypothesis that in women with chronic pelvic \npain in whom diagnostic lapa roscopy reveals either no pathol ogy or mild endometriosis \nlaparoscopic uterosacral nerve ablation (LUNA) a lleviates pain and improves life quality at \n12 months follow up. \nMethods \nA multi-centre, prospective, randomised-controlled-trial will be carried out with blind \nassessment of outcomes in eligible consenting patients randomised at diagnostic laparoscopy \nto LUNA (experimental group) or to no pelvic denervation (control group). Postal \nquestionnaires including visual analogue scale (VAS) for pain (primary outcome), an index of \nsexual satisfaction and the EuroQoL 5D-EQ instrument (secondary outcomes) will be \nadministered at 3, 6 and 12 months. The sample size has been estimated as 450 patients in \ntotal using the hypothesis that LUNA will moderately alleviate pain symptoms (i.e. 0.3 SD \ndifference in the pain scores on a VAS) compared to no intervention at one-year with 80% \npower at p= 0.05 and taking into consideration 20% loss to follow-up. The primary \nassessment of the effectiveness of LUNA will be from comparison of outcomes at the one-\nyear follow-up using intention to treat analysis. The medium-term and longer-term risks and \nbenefits of LUNA will also be evaluated at 2, 3, 5 and 10 years. \n 102\n\n  \nResults \nInterim analyses in 2004 have recommended continued recruitment. A total of 410 women \nhave been randomised (September 2004). The two groups are comparable in age, parity, type \nof chronic pelvic pain (CPP) and VAS baseline scores. \nConclusion \nThe LUNA trial is the largest trial of neuroablation thus far. It is hoped that if the results of \nthe trial are positive, women suffering from this common and difficult to treat condition will \nbenefit from this simple operation. If the results are negative a reliable basis for discouraging \nthe spread of this technique will have been provided. \n 103\n\n  \n \n7.2 INTRODUCTION \nThe transection of the uterosacral ligaments and the nerve plexuses it contains is a simple \nsurgical procedure for pelvic pain. The or iginal work by Doyle described vaginal and \nabdominal approaches to divide the attachment s of the uterosacral ligaments to the cervix. \n29;30 With the wider use of minimal access therapy there is a renewed interest in the division \nof the Frankenhauser nerve plexus in the uter osacral ligaments laparo scopically using lasers \nor electro-diathermy. In an attempt to reli eve patients’ symptoms clinicians frequently \nperform laparoscopic uterosacral nerve ablation (LUNA).  \nHowever the effectiveness of this proce dure has not been assessed objectively using \nmethodologically sound research. I conducted a survey of UK O&G consultants and European \ngynaecologists associated with the European Society of Gynaecological Endoscopy in 2002 \n(chapter 4) to determine the extent to which LUNA was being used in practice as also the \ndifferences in indications and techniques across Europe. I also conducted a survey of ‘prior \nbeliefs’ (chapter 5) to measure beliefs about effectiveness of LUNA. The survey indicated \nthat despite the lack of defi nitive evidence, many gynaecologist s familiar with the technique \nwere using LUNA as a therapeutic op tion. The systematic reviews to date 39;232 have indicated \nthe need for good quality trials to answer the que stion of effectiveness of this procedure in \nCPP. Crucially, the surv eys conducted in 1998 35 and 2002, both indicated that 93 of 108 \n(86%) gynaecologists currently performing LU NA were willing to r ecruit patients in a \nrandomised trial of LUNA. In this situation e quipoise applies i.e. th e technique has been \nintroduced without definite evidence but opinion regarding its use is not yet solidified. \n 104\n\n  \nHealth technology assessment in surgical interven tions requires an initial evaluation of the \nsafety and stability of new interven tions followed by randomised trials 233. The initial \nevaluative evidence 32;212 alone is not sufficient to assess the clinical effectiveness of LUNA \nfor which randomised research remains the gold standard.  \nUpdate of the Cochrane review (see chapter 6) has shown that the currently available \nrandomised research evidence on LUNA is also in conclusive. Therefore further research is \nrequired to generate effectiveness evidence in the form of a high quality randomised \ncontrolled trial. \n7.3 METHODS \n7.3.1 The LUNA trial Objectives  \n1. To test the hypothesis that in women with  chronic pelvic pain in whom diagnostic \nlaparoscopy reveals either no pathology or mild  endometriosis (Ameri can Fertility Society \nscore ≤ 5) LUNA alleviates pain and improves life quality at 12 months (principal objective). \n2. To test the hypothesis that response to LUNA differs according to the site and cause of the \npain by two secondary analyses: (i) Women with  central pain, (ii) women with no visible \npathology. \n3. To explore the variation in LUNA's effectiveness and side effects at different periods of \nfollow-up (3, 6, months and 1, 2, 3, 5 and 10 years). \n \nTo meet the above objectives, a multi-centre, pr ospective, randomised-controlled-trial funded \nby WellBeing (CF/371), 231 involving centres in the UK is being carried out with blinded \nassessment of outcomes in eligible consenting pa tients randomised and  blinded at diagnostic \n 105\n\n  \nlaparoscopy to LUNA (experiment al group) or to no pelvic denervation (control group). \nPostal questionnaires including visual analogue scale for pain (primary outcome), a sexual \nactivity questionnaire (SAQ) and the EuroQol 5D-EQ instrument (secondary outcomes) will \nbe administered at 3, 6 and 12 months. The prim ary assessment of the effectiveness of LUNA \nwill be from comparison of outcomes at th e one-year follow-up, although the medium-term \nand long-term risks and benefits of LUNA will also be evaluated by postal questionnaires to \nthe women at 2, 3, 5 and 10 years after laparoscopy. \n \nFigure 7.1: The laparoscopic uterosacral nerve ablation (LUNA) trial schema \nIdentification of eligible patient\n•Chronic pelvic pain >6mth\n•No obvious pathology\n•Informed consent\nRegistration of patient for LUNA\n•Complete pre-laparoscopy \nchecklist \n•Simple fax to BCTU\nFollow-upat 3, 6, 12, 24, 36, 60 and \n120 months by postal questionnaire\nNO LUNALUNA\nDuring laparoscopy\n•Complete at-laparoscopy checklist\n•Technically feasible\n•Freephone BCTU to receive \nallocation/ Internet randomisation\nIneligible patients:\nFollow-up at 6 & 12 months \nby postal questionnaire\n \n 106\n\n  \n7.3.2 Participants \nAll new patients presenting to the Gynaecology outp atient clinic with pelvic pain (cyclical or \nnoncyclical) and/or dyspareunia, and requiring di agnostic laparoscopy for evaluation of these \nconditions, will be invited to participate200.  \nInclusion criteria \nƒ Pelvic pain of longer than 6-month duration. \nƒ Pain located within the true pelvis or between and below the anterior iliac crests. \nƒ Associated functional disability. \nƒ Lack of response to medical treatment. \nƒ Diagnostic laparoscopy planned. \nExclusion criteria \nƒ Previous LUNA. \nƒ Mild, moderate and severe endometriosis (AFS score >5). \nƒ Previous surgery for endometriosis. \nƒ Previous surgery for pelvic inflammatory disease. \nƒ Previous hysterectomy. \nƒ Adnaexal pathology. \n7.3.3 Interventions \nDiagnostic laparoscopy plus uterosacral nerve ablation (experimental group) or laparoscopy \nwithout pelvic denervation (control group).  \nLUNA will be carried out in a uniform manner by named surgeons in each of the participating \ncentres following a common protocol as de scribed in the standard surgical text. 32 Routine \n 107\n\n  \npreparation will be made for a diagnostic la paroscopy with the patient under general \nanaesthesia. Following pneumoperitoneum, a laparosc ope will be used to visualize the pelvis. \nBefore embarking on operative laparoscopy an anatomical pelvic  assessment will be \nperformed to identify pelvic structures and pa thology. At this stage patients with pathology \noutlined in the exclusion criteria will be excluded. It is expected th at around 30% of women \nwill be unsuitable for LUNA at operation. Wo men who are ineligible for the LUNA trial \nbecause of moderate to severe endometriosis, significant adhesions, significant pelvic \ninflammatory disease, other significant pathology or those for whom LUNA is not technically \nfeasible should be registered  with the Trial Office for fo llow-up only. The woman should be \ntold that she was not eligible for the trial ra ndomisation and the reasons why, and asked if she \nwould agree to complete the follow-up questio nnaires at 6 and 12 months. This non-random \ncohort will provide comparative data on the natu ral history of patients with chronic pelvic \npain with significant pathology. Eligible patients will be randomised by a telephone call to the \nBCTU. \n \nClear identification of the uterosacral ligaments is a prerequisite to treatment with lasers or \nelectro-diathermy. The posterior leaf of the broad ligament will be carefully inspected to \nidentify the course of the ureters, which on rare  occasions could be particularly close to the \nuterosacral ligaments. Care will also be taken to note thin walle d pelvic veins, which often lie \nlateral to the uterosacral lig aments. If accidentally punctured, they may cause troublesome \nbleeding requiring further endoscopic endocoagul ation. The uterosacral ligaments will be \nidentified by manipulation of the uterus in the right and left lateral planes. The ligaments will \nthen be ablated with laser or micropoint electro-diatherm y or endocoagulation depending \nupon the surgeons’ preference. The variation in th e surgical techniques is as noted in Chapter \n 108\n\n  \n4. In a typical case, the ablation will start as cl ose to the posterior aspect of the cervix as \npossible and continue for a minimum of 1 cm po sterolaterally on either  side. The aim of the \nprocedure is to destroy the sens ory nerve fibres and the seconda ry ganglia as they leave the \nuterus and come to lie within the uterosacral ligaments.  \nThe safe conduct of operative laparoscopy for LUNA requires the use of two ports, one for \ndelivery of the energy source (l aser or diathermy) and anothe r for manipulation. These are in \naddition to the umbilical port  used for the laparoscope it self. In contrast, diagnostic \nlaparoscopy in women with no pathology requires only one port in addition to the umbilical \nlaparoscopic port. This difference in number of  ports has potential for introducing bias by \ncompromising patient blinding to  group allocation. A sham incision (see discussion) in the \ncontrol group is used to overcome this problem. \n7.3.4 Trial procedures \nConsenting eligible patients will be randomised  to diagnostic laparoscopy plus uterosacral \nnerve ablation (experimental gr oup) or to no pelvic denerva tion at the time of diagnostic \nlaparoscopy (control group).  \nThe subjects will be allocated to groups using a chance procedure, blocking and stratification. \n234 Stratified block randomisation will be employed to ensure that there will be nearly equal \nnumbers of patients in the two groups within the prognostic subgroups, even if the study ends \nprematurely. Variable block size will be used to avoid any possibility of foreknowledge.  \nRandomisation will be conducted using minimisation, stratified by the four variables: \na. Presence or absence of some minimal pathology (minimal endometriosis ± ablation; \nadhesions requiring adhesiolysis only; minimal pelvic inflammatory disease) \n 109\n\n  \nb. Site of pain (presence of central pain or not) \nc. Parity of the woman (nulliparous or parous) \nd. Whether the woman is sexually active or not \nThe first two variables form the prespecified  subgroup analyses, and th e other two variables \nare included as having impact on dysmenorrhoea and dyspareunia respectively. \n \nTreatment allocation will be issued at diagnos tic laparoscopy, after the surgeon has inspected \nthe pelvis and ensured that the patient fulfils all of the inclusion criteria and she does not have \nany of the exclusion criteria. Women may be randomised or registered into the study by \ntelephoning the toll free Randomisati on Line on 0800 953 0274 (+44 121 687 2319 from \noutside the UK) or by Internet randomisation at http:// www.trials.bham.ac.uk/luna and \nclicking on the randomisation button. Passwords for Internet randomisation will only be \nallocated to centres with ethical approval. \nFollowing surgery, the surgeon fills in operation details on a post-surgery form. (Appendix 6) \nPatients will be kept blind to their treatmen t allocation until the follow-up in the trial is \ncomplete. However, there is a potential problem  in the maintenance of blinding in the LUNA \ntrial. As mentioned earlier, patients allocated to have LUNA will  have the standard operative \nlaparoscopy with three ports (one 10mm umbilical port and two 5mm lateral ports), whereas \npatients allocated to the control group under normal circumst ances would have standard \ndiagnostic laparoscopy with two ports (one 10 mm umbilical port and one 5mm lateral or \nmidline port). By noting the different number of  incisions some patients might become aware \nof their group allocatio n and this might alter their response. In order to maintain patient \n 110\n\n  \nblinding, a sham 5mm skin incision is made superf icially in a lateral por t site. This approach \nin avoiding bias due to lack of blinding has been used in a previous trial of laparoscopic nerve \nablation 221 and has also received ethical approval in this trial. \nThe trial is being managed from the BCTU. Each  investigating centre will carry out the study \nin accordance with the study protocol and to  the Medical Research  Council guidelines on \nGood Clinical Practice in Clinical Research (1998). Patients will be invited to participate if \nthey fulfill all the inclusion criteria and do not have any exclusion criteria. They will be \nprovided with a laparoscopy and LUNA trial information leaflet and signed consent obtained \nprior to laparoscopy. Consenting patients w ill be asked to complete the Enrolment \nQuestionnaire and On Study Form. The final decision to enroll patient in the trial will depend \non the findings at laparoscopy when the surgeo n will perform LUNA or not after determining \neligibility as shown in Eligibility Ch ecklist and Randomisation Fo rm. At the end of the \nprocedure the surgeon will complete the Post  Surgery Form (Appendix 6 contains all the \nforms used in this trial). All the three forms for each patient enrolled will be photocopied to \nkeep a record at the participating centre and the originals will be sent to the BCTU, which will \nact as the coordinating centre.  At 3, 6 and 12 months afte r enrolment, the Follow-up \nQuestionnaire will be mailed to the patients with a pre-paid self-addressed envelope. \nRecruitment is expected to take 12 months ( upto September 2005) and follow up for the main \nendpoints another 12 months. At completio n of the main study further follow-up \nquestionnaires will be mailed out at 24 and 36 months. \n 111\n\n  \nTable 7.1: Study Flow Chart \nGynaecology \nClinic \nOperating \nTheatre \nPostal Follow up (months/ years) Form/Questionnaire \n  3 6 12 2 3 5 10 \nPatient information and \nconsent (Appendix 6.1) \nX          \nEligibility Checklist and \nRandomisation form \n(Appendix 6.2)  \nX  X         \nEnrolment Questionnaire \n(Appendix 6.3) \nX          \nSurgery Form (Appendix \n6.4) \n X         \nLetter to GP (Appendix \n6.5) \nX          \nFollow-up Questionnaire \n(Appendix 6.6) \n  X X X X X X X \n \n7.3.5 Outcomes \nThe primary outcome measure will be based on VAS for assessment of pain. 235 This \ntechnique involves use of a 10 cm line on a piece of paper representing a continuum of the \npatients' opinion of the degree of pain. It is explained to the patient that the one extreme of the \nline represents “no pain at all” while the othe r represents “as much pain as she can possibly \nimagine”. The subject rates the degree of pain by placing a mark on the line and scale values \nare obtained by measuring the distance from zero to that mark.  \n \n 112\n\n  \nThe secondary outcome measures will be assessment of sexual function and quality of life. \nThe Sexual Activity Questionnaire (SAQ) 236 will replace the Brief Index of Sexual \nSatisfaction (BISS) 237 for the assessment sexual function. This has been necessitated due to \nthe poor acceptability and comp liance with BISS in the pilot study. The SAQ has excellent \ninternal consistency and test retest reliability. It also has excellent c oncurrent and construct \nvalidity and has been shown to be acceptable to women in other clinical trials. 238 In the \nquestionnaire it will be clearly stated that the measure of sexual function covers material that \nis sensitive and personal. Participants will be reassured that their responses will be kept \ncompletely confidential and that if they do no t wish to answer any questions, they will be \nallowed to leave the questionnaire blank.  \nHealth-related quality of life (HRQL) instru ments are becoming powerful tools for outcome \nassessments in randomised trials. Quality of life  instruments assess aspects of patient’s health \nstatus usually not grasped by conventional clini cal indices; hence, they can be applied as \ncomplementary assessments together with VAS a nd SAQ. Quality of life has to be defined \nclearly and patient’s perception of  normal performance serves a pi votal role in this context. \nHRQL instruments are administered with qu estionnaires assessing a number of different \ndomains, i.e. areas of behavior or experience that the instrument is attempting to measure. 239 \nEconomic outcomes are often considered in clinical trials. LUNA is a quick, safe and \ninexpensive procedure for women already undergoing diagnostic laparoscopy. Our hypothesis \nis about a clinically important effect without an excess of comp lications. If the hypothesis is \nconfirmed, then any benefits will essentially be “dominant” outweighi ng the relatively small \ncosts of intervention. Therefore, we do not plan  a formal economic evaluation at this stage. \nHowever, data on health resource use will be  collected partly as effectiveness outcome \nmeasures (i.e. less need for medical care for pelv ic pain indicates grea ter effectiveness), and \n 113\n\n  \npartly to allow an economic evaluation to be  carried out, should significant complications \noccur. Other measures will include analgesic use, consultations at general practice and \nhospital, and time off work. Again these ar e both economic outcomes and indicators of \nresidual pain. \nPostal Questionnaires to assess pain and sexual function will be administered at enrolment in \nthe trial and then at 3, 6, 12, 24 and 36 months  after laparoscopy. The outcomes at 12 months \nwill be used to address the primary research question. This time interval is chosen because \nlaparoscopy alone has a placebo effect for up to 3-6 months in some patients. \n71;240 The 24 and \n36-month follow up will be used to monitor medium-term effects of the intervention. Existing \nparticipants in the trial who consented to 3 years of follow-up will be asked to consent to \nlong-term follow-up (10 years) once they have  reached the 3 year follow up time-point. \nParticipants randomised after June 2003 are asked to consent to 10 years of follow-up at entry \nfor long term follow up. \nThe centres have been advised to fill an “adverse event form” in case of immediate and \ndelayed complications if any are associated with the procedure.  \n7.3.6 Sample Size and Power Considerations \nThe sample size for this trial has been es timated using the hypothesis that LUNA will \nalleviate pain symptoms (i.e. reduce pain scores on a VAS) more often than no intervention at \none-year following diagnostic laparoscopy. Cohe n describes 'effect sizes' of 0.2 and 0.5 \nstandard deviations (SD) as 'small' and 'medium'. 241 Interim analyses of the pilot study \nindicate that the SD of the difference in cha nge in VAS scales between LUNA and no pelvic \ndenervation groups will be about 4.0. This corres ponds to small and medium effect sizes on \n 114\n\n  \nVAS of 0.8 and 2.0 respectively an d is consistent with  other studies of chronic pelvic pain, \nwhere clinically important symptom alleviation has been defined as a reduction in pain score \nof 2 or more 242. To confirm or refute a small to medium effect of LUNA (0.3 SD difference \nor 1.2 VAS points), based on ά=0.05 and β=0.2 (80% power), 175 patients in each group (i.e. \n350 patients in total) will be required. Considering a 20% loss to follow-up, the sample size is \ninflated to 210 patients in each group (i.e. 420 patients in total). \n7.3.7 Data Analysis \nThe type of analysis will be based on Intention to treat principles. The main analysis to \naddress the principal research questions will be conducted using the one-year follow-up data. \nThe mean differences in VAS pain scores; sexu al satisfaction and life quality scores in the \ntwo groups will be compared using a two-sample t-test. The rates of wo men with clinically \nsignificant (2 VAS point) alleviation of pain symptoms will also be compared producing a \nrelative risk estimate with 95% confidence intervals (Mantel-Haenzel test). Baseline \ncharacteristics of the patients enrolled in th e two groups will be compared to ensure that \nrandomisation has produced comparable groups of patients. The use of additional treatment \n(co-intervention) for pelvic pain following LU NA or no pelvic denervation will be assessed \nfor any systematic difference between the two groups.  \nSubgroup analyses are limited by statistical power and can produ ce spurious results \nparticularly if many are under taken. Our literature review 39 and consultation with \ngynaecologists 35 suggests that the effectiveness of  LUNA may be greater for central \ncompared to non-central pain and if there is no associated pathology (i.e. no endometriosis). \nTherefore, we have chosen to limit secondary  analyses to these subgroups only. The LUNA \ntrial is powered to detect a small to medium overall difference and if a larger treatment benefit \n 115\n\n  \nis found then other subgroup analyses will be undertaken, appropri ately cautiously. The \nLUNA trial is powered overall at  80% to detect a 0.3 SD differe nce in effect. Our pilot study \nshows that 60% patients have mainly central pain and 70% have no pathology. Hence, in the \nsubgroup with central pain the power will be 80% to detect a 0.4 SD treatment effect. In the \nsubgroup with no pathology the power will be 80% to detect a 0.35 SD treatment effect.  \n \n7.4 RESULTS \nA study was undertaken with the objective of asse ssing its feasibility of a trial of LUNA. It \nhas shown acceptability to patients. It has al so established trial management procedures, \npiloted questionnaires, measured compliance and standardised operating procedures. A \nconfidential interim analysis was reviewed by an independent data monitoring committee \nwhen the first 60 patients had completed 6 months follow-up (March 2001). The committee \nrecommended that a larger study is needed for adequate statistical pow er in the trial to \nevaluate LUNA reliably.  \nBi-annual analyses of recruitment, compliance and loss to follow-up are being carried out for \nLUNA Trial Management Committee. An annual interim analysis of ef fectiveness was done \nin March 2003 and 2004 for confidential revi ew by independent Data Monitoring Committee \nto determine whether the principal question has been answered and to monitor adverse events. \nIt confirmed sample size estimation and recommended continued recruitment into the trial. \n \nInterim analysis has provided with the details of the baseline characteristics of women \nrecruited in the trial upto August 2004 as described in the table below. \n 116\n\n  \nTable 7.2: Baseline characteristics of participants in the LUNA trial. Items marked * were, \nuntil recently, asked on the “On Study Form” rather than the randomisation form, and would therefore only be \npresent if such a form were returned. Items marked ** were not asked on all versions of this form so information \nis necessarily not complete. \n LUNA No LUNA \nNumber randomised 200 206 \nTreatment received* \nLUNA \nNo LUNA \nUnknown \n \n182 \n3 \n15 \n \n0 \n186 \n20 \nAge: \n17-19 \n20-29 \n30-39 \n40-49 \n \n7 \n64 \n89 \n40 \n \n6 \n74 \n83 \n43 \nAdhesions Present 40 35 \nEndometriosis \nNone \nMinimal \nMinimal, Ablated \n \n150 \n32 \n18 \n \n142 \n42 \n22 \nPelvic Inflammatory Disease 3 9 \nGravida* \n0 \n1 \n2 \n3 \n4+ \nUnknown \n \n56 \n27 \n36 \n26 \n22 \n33 \n \n75 \n24 \n31 \n18 \n26 \n32 \nPara* \n0 \n1 \n2 \n3 \n4+ \nUnknown \n \n71 \n31 \n43 \n18 \n13 \n24 \n \n75 \n33 \n43 \n19 \n14 \n22 \nSexually Active* \nYes \nNo \nUnknown \n \n160 \n30 \n10 \n \n152 \n33 \n21 \nDysmenorrhoea* \nPresent \nAbsent \nUnknown \n \n146 \n43 \n11 \n \n144 \n51 \n11 \nDyspareunia* \nPresent, Sexually Active \nAbsent, Sexually Active \nNot Sexually Active \nUnknown \n \n127 \n29 \n30 \n14 \n \n110 \n41 \n33 \n22 \nNon-menstrual pain* \nPresent \nAbsent \nUnknown \n \n125 \n58 \n17 \n \n126 \n67 \n13 \n 117\n\n  \n LUNA No LUNA \nAny visible pathology: \nYes \nNo  \n \n15 \n185 \n \n11 \n195 \nCentral dysmenorrhoea* \nYes \nNo \nUnknown \n \n93 \n92 \n15 \n \n96 \n96 \n14 \nCentral dyspareunia* \nYes \nNo \nUnknown \n \n92 \n88 \n20 \n \n89 \n105 \n12 \nCentral Non-cyclical pain* \nYes \nNo \nUnknown \n \n54 \n126 \n20 \n \n58 \n132 \n16 \nIrritable Bowel Syndrome** \nYes  \nNo \nUnknown \n \n1 \n76 \n123 \n \n0 \n82 \n124 \nPrevious Laparoscopy** \nYes \nNo \nUnknown \n \n1 \n42 \n157 \n \n3 \n45 \n158 \nPrevious Surgery** \nYes \nNo \nUnknown \n \n0 \n78 \n122 \n \n2 \n81 \n123 \nCentral pain: Any* \nYes \nNo \nMissing/Unclear \n \n130 \n52 \n18 \n \n136 \n54 \n16 \n \n 118\n\n  \nTable 7.3: Baseline VAS scores of pain, EUROQoL scores and sexual satisfaction scores \nof participants in the LUNA trial \n \nLUNA No LUNA \nBaseline VAS - dysmenorrhoea \nN \nMean, SD \n \n \n170 \n6.56 (2.63) \n7.2 (5 – 8.6) \n \n176 \n6.7 (2.39) \n7.1 (5.2 – 8.4) \nBaseline VAS - dyspareunia \nN \nMean, SD \n \n \n156 \n5.9 (3.1) \n6.5 (4 – 8.5) \n \n169 \n5.3 (2.97) \n5.7 (3 – 7.7) \nBaseline VAS – other pain \nN \nMean, SD \n \n \n167 \n5.7 (2.7) \n5.8 (4.1 – 8) \n \n177 \n5.9 (2.73) \n6.5 (4.3 – 8) \nBaseline EuroQol Thermometer \nN \nMean, SD \n \n \n153 \n65.8 (22.75) \n70 (50 – 85) \n \n161 \n67.9 (21.13) \n75 (50 – 85) \nBaseline EuroQoL Health Status \nN \nMean, SD \n \n \n167 \n0.56 (0.32) \n0.72 (0.23 – 0.8) \n \n167 \n0.58 (0.3) \n0.73 (0.23 – 0.8) \nBaseline Sexual Satisfaction Score \nN \nMean, SD \n \n \n136  \n21.7 (14.85) \n18 (9 – 31) \n \n130 \n23.8 (16.29) \n21 (21 – 34 \nEuROQoL-European Quality of life questionnaire; SD- standa rd deviation; VAS- visual \nanalogue scale \n 119\n\n  \nFigure 7.3: Quarterly recruitment progress in the LUNA trial \nQuarterly Recruitment Chart\n0\n5\n10\n15\n20\n25\n30\n35\n40\n45\n50\nFeb 98 -\n Apr\n 98\nAug 98 -\n Oct 98\nFeb 99 - Apr 99Aug 99 - Oct 99Feb 00 -\n Apr\n 00\nAug 00 - Oct 00Feb 01 - Apr 01Aug 01 -\n Oct 01\nFeb 02 -\n Apr\n 02\nAug 02 - Oct 02Feb 03 -\n Apr\n 03\nAug 03 -\n Oct 03\nFeb 04 - Apr 04Aug 04 - Oct 04\nNumber of Patients Randomised\n \n* Indicates incomplete quarter \nThe graph above indicates the rate of recruitmen t divided in quarters in the LUNA trial. As \nseen in the graph, the recruitment increased once a dedicated research fellow was appointed to \ncoordinate the trial. The recrui tment is above target in most months (target is 15/month at \npresent) and is expected to finish by April 2005 if the recruitment is car ried on at the current \nrate of approximately 18/ month. This projecti on of recruitment is illustrated in the graph \nbelow (figure 7.5). \n \nThe recruitment is highest in the centres where there is a Research fellow or funded research \nnurse sessions (BWH, Forth Park Hospital, Royal Hallamshire Hospital) \n \n 120\n\n  \nFigure 7.5: Recruitment Projection in the LUNA trial \n0\n50\n100\n150\n200\n250\n300\n350\n400\n450\nFeb-98\nAug-\n98\nFeb-9\n9\nAug-99Feb-0\n0\nAug-00Feb-0\n1\nAug-01Feb-0\n2\nAug-02Feb-0\n3\nAug-03Feb-0\n4\nAug-0\n4\nFeb-0\n5\nNumber of patients randomised\nSeries1\nSeries2\nSeries3\nSeries4\n \n \nFigure 7.4: Recruitment by collaborating centres until August 2004 \nRecruitment by Centre\n0102030\n405060\n708090100110120\n130\n140150160\n170180190\n200210220\n230240250\nBirmingham\nWomens Hospital\nCity Hospital\nHeartlands Hospital\nNew Cross\nHospital\nNinewells Hospital\nPerth Royal\nInfirmary\nRoyal Hallamshire\nHospital\nStafford General\nHospital\nForth Park\nWalsgrave Hospital\nNottingham City\nHospital\nSandwell Hospital\nBurton District\nHospital\nNorthampton\nNumber Randomised\n \n 121\n\n  \n7.5 DISCUSSION \n7.5.1 Main findings \nThe acceptance rate for women invited to participate in the trial currently is 70%. The \nbaseline characteristics of women randomised in  the trial are not appr eciably dissimilar. The \nfollow up rate at present is 71% and efforts are being made to improve it.  \n7.5.2 Quality of the trial \nThe trial report will aim to convey to the reader  the information needed to make informed \njudgments regarding the internal and external validity of the trial. LUNA trial complies with \nall the quality criteria laid down in the CONSORT checklist\n243 as is shown in table7.4 \n \nLUNA Trial design ensures adequa te methodological quality as it has taken care of selection \nbias (secure randomisation and allocation of participants), perfor mance bias (blinding), \nmeasurement bias (valid and reliable pain measurement over long term) and statistical \nuncertainty (use of a power cal culation) amongst other features. Stratified allocation is used \nso that chance imbalances in the stratification variable do not have an  effect on the outcome. \nAs has been previously pointed out in chapter 4,  there are several acceptable variations in the \npractice and techniques of LUNA. Since respons e to treatment may depend on the surgeons' \ntechnique for laparoscopic uter osacral nerve ablation, analyses will be retrospectively \nstratified according to the surgeons participa ting in the trial. Allocation concealment is a \ncrucial factor in avoiding bias in randomised trials. 244 Although it is not possible to blind the \nsurgeon, it is essential to keep the surge on blind to the group allocation until after the \nirrevocable decision to enter the woman into the trial has been made. \n 122\n\n  \nTable 7.4 Consolidation of standards for Reporting Trials (CONSORT) checklist \napplied to the LUNA Trial Protocol \nHeading Subheading Descriptor Reported\nTitle  Identify the study as a RCT √ \n \nAbstract  Use a structured format √ \n \nIntroduction  State prospectively defined hypothesis, clinical objectives and \nplanned subgroup analysis \n√ \n \n \nMethods Protocol Describe: \nPlanned study population with inclusion and exclusion criteria \nPlanned intervention and their timing \nPrimary and secondary outcome measures and minimum \nimportant differences and indicate how the target sample was \nprojected \nRationale and methods of statistical analysis, detailing main \ncomparative analyses and whether they were completed on ITT \nbasis \nProspectively defined stopping rules (if warranted) \n \n√ \n√ \n√ \n \n√ \n√ \n√ \n Assignment Describe \nUnit of randomisation \nMethod used to generate allocation schedule \nMethod of allocation concealment and timing of assignment \n \n \n√ \n√ \n√ \n Blinding Describe mechanism, allocation schedule control and evidence of \nsuccessful blinding among participants, outcome assessors, and \ndata analysis \n \n√ \n \n \nResults Participant \nFlow& Follow \nup \nProvide a trial profile summarizing participant flow, numbers and \ntiming of randomization assignment, interventions, and \nmeasurements for each randomized group \n \nN/A \n Analysis State estimate effect of intervention on primary and secondary \noutcome measures including a point estimate and measure of \nprecision (confidence interval) \nDescribe prognostic variables by treatment group and any attempt \nto adjust for them \n \n√ \n \n \n \n√ \nComment  State interpretation of study findings, including source of bias and \nimprecision (internal validity) and discussion of external validity \nincluding appropriate quantitative measures when possible \n \n√ \n \n \n \n \n \nPatients may also show a placebo effect if they know they have received the \nactive treatment. The magnitude of  placebo effects should not be \nunderestimated. There is clear evidence that inadequacies of blinding in \nrandomisation lead to exaggeration of tr eatment effect in randomised trials. A \n 123\n\n  \nsecond purpose of blinding is to prevent differences in other aspects of patient \nmanagement introducing bias es affecting the results. 244 The patient’s GP will \ntherefore be kept blind to treatment a llocation.  Double blinding is not possible \nin LUNA, however, as the surgeons performing the surgical  intervention on the \npatients will be aware of the group alloca tion. However, the likelihood that this \nwill lead to bias in outcome assessment is low as the patient outcome \nassessments in this study will be conducted by self-administered questionnaires, \navoiding any possible bias from surgeons’ knowledge of group allocation. \nPain is difficult to measure, partly because it is accompanied by other \nsensations and partly because the reaction component  affects the judgment of \nthe pain regardless of the intensity of the stimulus. A measure of pain is \nnevertheless essential to the outcome of this clinical trial. VAS originally \ndevised as measures of well being,\n245 have been successfully adapted to \nmeasure pain and have been establis hed to be reproducible and accurate. 235;246 \nVAS has commonly been used in measurement of chronic pain. 247 All the \nstudies of LUNA included in systematic reviews so far have used this measure, \nor its variation, for assessing outcome. Individual pain scores have sufficient \npsychometric strengths to be used in chronic pain resear ch involving group \ncomparison designs.248 Sexual function is an important  aspect of life quality in \npatients with pelvic pain. Pain itself is an anti-aphrodisiac, and together with \ndiscomfort and altered self-ima ge, it impacts upon sexual function. \n249 Its \nassessment in an objective manner is ther efore an important part of the LUNA \ntrial. There are several sexual functi on instruments, with high levels of \nreliability, validity and responsiveness, which yield comparable results across \n 124\n\n  \noccasions and individuals, making them suitable for monitoring therapeutic \nprogress in randomised research. 249 \nWhen there is uncertainty about the appropr iate therapy, scientific clinical trials \nare the best scientifically ethical way to  resolve uncertainty and thereby benefit \nboth the individual patients and all others concerned in their care. 250 The need \nfor a “sham” incision in this trial is the main ethical issue and it is required \nbecause without it the patients cannot be kept blinded. The purpose of blinding \nis to prevent various biases from affecting the results. The need for blinding in \nsurgical trials has been emphasized in the medical literature \n251 and there is \nempirical evidence that inadequacies of  blinding in randomisation lead to \nexaggeration of therapeutic efficacy in randomised trials.244 Blinding of patients \nin surgical trials is clearly indicated when the intervention primarily treats \nsymptoms and when the outcomes are based on patients' own assessment. \nLUNA is an intervention for treating chr onic pelvic pain (a diagnosis based on \nsymptoms) and the outcome assessment is based on patients’ responses on a \nVAS and a quality of life instruments. He nce, the use of a “sham” incision is \njustified if bias is to be avoided in the LUNA trial and this approach has been \nused in a previous trial of LUNA.\n221 Ethical approval for the LUNA trial \nprocedures has already been obtained fr om the Multicentre Research Ethics \nCommittee. \n \nThe LUNA trial is already the largest trial of neuroablation. It is hoped that if \nthe results of the trial are positive, women suffering from this common and \n 125\n\n  \ndifficult to treat condition will benefit from this simple operation. If the results \nare negative a reliable basis for discouraging the spread of this technique will \nhave been provided. \n 126\n\n  \nCHAPTER 8 SUMMARY \n 127\n\n  \n8.1 Summary of findings \nIn this thesis, I have collated existing know ledge on prevalence and aetiology of chronic \npelvic pain and effectiveness of pelvic ne uroablation by means of thorough systematic \nreviews. I have surveyed practice of LUNA in  Europe, developed que stionnaire to collect \n‘prior beliefs’ on effectiveness of LUNA and LUNA trial protocol. Below, I reproduce the \ntable of structured questions from Chapter 1 (Table 1.1), adding a final column of results from \nthe various chapters of this thesis:  \n \n 128\n\n  \nTable 8.1: Findings of the objectives in the thesis \n \nObjective A: To summarise the evidence on prevalence and aetiology of chronic pelvic pain with systematic reviews of \nrelevant studies \nCha\npter  \nPopulation Comparison  \n \nOutcomes Research Design Findings \n2 Women at \nrisk \nPrevalence by \nrepresentative\nness of \nstudies \nDysmenorrhoea \nDyspareunia \nNoncyclical pelvic \npain (CPP) \n \nSystematic review \n(SR) of observational \n(cross sectional or \nlongitudinal) studies \nThere was significant variation among rates \nof all three types of CPP. Meta-analysis of \nrates amongst high quality studies with \nsamples representative of general \npopulation showed that prevalence of \ndysmenorrhoea (12 studies) was 59% (95% \nCI 49.1-71%), of dyspareunia (11 studies) \nwas 13.3% (95% CI 8.8-20.3%) and of \nnoncyclical pain (2 studies) was 6.2% \n(95% confidence interval (CI) 3-12.6%, \nheterogeneity p for all three values was \n<0.001).  \n \n3 Women at \nrisk \nGeneral, \nGynaecologi\ncal/ \nobstetric,  \nPsychologic\nand social \nfactors \nDysmenorrhoea \nDyspareunia \nNoncyclical \npelvic pain \n \nSR of observational \n(cohort, case-\ncontrol or cross \nsectional) studies \nthat provide \ncomparative \ninformation on \npresence of risk \nfactors in women \nwith or without \nCPP \nThere were 122 studies (in 111 articles) of \nwhich 63 (64,286 women) evaluated 54 \nrisk factors for dysmenorrhoea, 19 (18,601 \nwomen) evaluated 14 risk factors for \ndyspareunia and 40 (12,040 women) \nevaluated 48 factors for noncyclical CPP. \nAge less than 30 years, low BMI, smoking, \nearly menarche (<11 years), longer cycles, \nlonger duration of bleeding or heavy \nmenstrual flow, nulliparity, premenstrual \nsyndrome, sterilisation, PID, sexual assault, \nemotional difficulties, psychological \nsymptoms and somatisation were \nassociated with increased risk of \ndysmenorrhoea. Younger age at first \nchildbirth, exercise and oral contraceptives \nand were associated with reduction in the \nrisk of dysmenorrhoea. Age less than 50 \nyears, peri/post menopausal state, PID, \nsexual abuse, anxiety and depression were \nfound to be associated with dyspareunia. \nDrug/alcohol abuse, miscarriage, heavier \nmenstrual flow, PID, previous caesarean \nsection, pelvic adhesions/other pathology, \nchildhood physical or sexual abuse, \nlifetime sexual abuse, anxiety, depression, \nhysteria, psychosomatisation were \nassociated with an increased risk of \nnoncyclical pelvic pain \n \n 129\n\n  \n \nObjective B: To examine the variation in current indications and surgical techniques for performing \nlaparoscopic uterine nerve ablation (LUNA) in Europe and assess the effect of operator experience on practice \nas also to explore gynaecologists’ ‘prior’ beliefs on effectiveness of LUNA \n4 Gynaecologists \nin the UK and \nrest of Europe \nStructured \nquestionna\nire  \nIndications and \ntechniques for \nLUNA across \nEurope \n \n \nSurvey The questionnaire was returned by 719 \n(38% of 1870) of the gynaecologists \ncontacted and 173 (24%) performed \nLUNA. Indications for LUNA were similar \nacross UK and rest of Europe. The \nEuropean group performed LUNA more \noften (62% vs. 21%), completely transected \nthe uterosacral ligaments (56% vs. 36%) \nand ablated at a distance of more than 2 cm \nfrom its cervical insertion (50% vs. 21%) \nmore frequently than the UK group. More \nexperienced gynaecologists performed \nLUNA more for dyspareunia (46 % vs. \n26%) and endometriosis (67% vs. 47%) \nand they performed complete transection \n(45% vs.26%) more often than their less \nexperienced counterparts. \n \n5 Gynaecologists \ncollaborating in \nLUNA trial \nStructured \nquestionna\nire  \n‘Prior beliefs’ \non effectiveness \nof LUNA \n \nSurvey The most widely held ‘prior’ belief, \nreflected in both questionnaire and \nnumerical responses was that LUNA would \nhave a small beneficial  effect on pain. The \ncredible limits of this belief were \ncompatible with large reductions in pain as \n60% of respondents believed a three-point \nimprovement on VAS to be plausible. The \nstandard deviations of expected mean \nchange in VAS due to LUNA ranged from \n0.52 to 1.64.  \n \n 130\n\n  \n \nObjective C: To determine the effectiveness of neuroablation in CPP by means of a systematic review and \ndevelop a protocol for a prospective randomised controlled trial to assess the effectiveness of LUNA in CPP \n6 Women \nundergoing \nlaparoscopy \nfor CPP \nNeuroablative \nprocedures \n(LUNA or \npresacral \nneurectomy \n[PSN]) versus \nno \nneuroablation \nPain relief  \nAdverse effects \nCochrane SR Nine RCTs were included in the systematic \nreview. There were two trials with open \npresacral neurectomy (PSN); all other trials \nused laparoscopic techniques. For the \ntreatment of primary dysmenorrhoea, \nLUNA at 12 months was better when \ncompared to a control or no treatment (OR \n6.12; 95% CI 1.78-21.03). The comparison \nof LUNA with PSN for primary \ndysmenorrhoea showed that at 12 months \nfollow up, PSN was more effective (OR \n0.10; 95% CI 0.03-0.32). In secondary \ndysmenorrhoea, along with laparoscopic \nsurgical treatment of endometriosis, the \naddition of LUNA did not improve the pain \nrelief (OR 0.77; 95% CI 0.43-1.39) while \nPSN did (OR 3.14; 95% CI 1.59-6.21). \nAdverse events were more common for \nPSN than procedures without PSN (OR \n14.6; 95% CI 5-42.5). \n \n7 Women with \nCPP who \nneed \ndiagnostic \nlaparoscopy \nLUNA versus \nNo LUNA \nduring \nlaparoscopy  \nImprovement in \nCPP, quality of \nlife and sexual \nfunction \nMulticentre randomised \ncontrolled trial protocol \nInterim analyses in 2004 have \nrecommended continued recruitment. A \ntotal of 410 women have been randomised \n(September 2004). The two groups are \ncomparable in age, parity, type of chronic \npelvic pain (CPP) and VAS baseline \nscores. \n \n \n8.2 Implications for clinical practice \n• Prevalence of dysmenorrhoea (12 studies) is 59% (95% CI 49.1-71%), of dyspareunia \n(11 studies) is 13.3% (95% CI 8.8-20.3%) and of noncyclical pain (2 studies) is 6.2% \n(95% CI 3-12.6%). This precise estimation of disease burden should be considered by \npolicy makers when planning gynaecological services. \n• Key gynaecological and psychosocial factors associated with CPP should be targeted \nin clinical evaluation of women with this symptom to individualize their management. \n• There is variation in the surgical techniques of performing LUNA in Europe and the \ntechniques vary according to operator experience. This variation may impact on \n 131\n\n  \neffectiveness of LUNA. LUNA trial when completed will shed light on effectiveness \naccording to technique. \n• Among gynaecologists, there is a variation in beliefs about the effects of LUNA on \npelvic pain, ranging from substantial benefit to slight harm. Gynaecologists may take \nthis into account when judging the results of the LUNA trial, which may affect the \nuptake of LUNA trial’s findings. \n• The evidence to recommend the use of nerv e interruption in the management of \ndysmenorrhoea, regardless of cause, is current ly insufficient. This information should \nform part of patient’s counselling at present. \n \n8.3 Implications for research practice \n• Substantial differences or even complete absence of definitions, together with \ndifferences in age ranges of the populations studied, complicate the interpretation of \nprevalence of CPP. The surveys should use the validated measurement tools for \nvalidity and comparability of the results \n• Use of retrospective studies which are subj ect to incomplete or selective recall of \nprevious events, inappropria te exposure comparisons in some studies, use of non-\nstandard measurement tools with questionable validity or reliability, selecting control \ngroups from women consulting for other conditions in the same setting, who did not \nhave assessment like laparoscopy, non use of  explicit definition for CPP and other \nsuch factors reduce the ability to conf idently investigate causation. Future \nepidemiological studies should ideally be pros pective, with explic it definitions of the \noutcome and representative of the general population.  \n 132\n\n  \n• The development of non-invasive diagnostic tools for some of the underlying somatic \nconditions that may account for CPP will help with unraveling of some of the risk \nfactors further. If treatment of pathology in CPP shows no better outcome than without \ntreatment, then probably there is role for trials in psychological interventions. It would \nbe rational to design intervention studies of use of psychological counseling, \nantidepressants and other modifiable factors in chronic pelvic pain. \n• Methods of documenting distribution of beliefs about likely effects of a treatment need \nfurther development. It would also be interesting to compare the graphical and textual \nmethods of collecting “Bayesian priors” and explore the factors that potentially will \nlead to better representation of the clinicians’ opinions \n• The uncertainty about the effectiveness of neuroablation in CPP indicates that \nscientific clinical trials are the best way to resolve uncertainty. Another efficient \nalternative would be an individual patient data metanalysis of all the existing trials and \nongoing studies  \n 133\n\n  \nTABLE OF CONTENTS OF APPENDICES  \n(Appendices appear in the accompanying CD ROM) \n \nAppendix 1: Supplementary information on Chapter 1: Introduction………………………3 \nAppendix 1.1: Contributions to the Chapters of the thesis………………………………… 4 \nAppendix 2: Supplementary data for Chapter 2: Systematic review of prevalence of  \nchronic pelvic pain………………………………………….………………………… 9 \nAppendix 2.1: Medline search strategy for systematic review of worldwide prevalence  \nof chronic pelvic pain………………………………………………………………….. 10 \nAppendix 2.2: List of included studies in the systematic review of worldwide prevalence  \nof chronic pelvic pain…………………………………………………………………… 12 \nAppendix 2.3: Table of included studies on dysmenorrhoea……………………….. 26 \nAppendix 2.4: Table of included studies on dyspareunia…………………………… 71 \nAppendix 2.5: Table of studies included on noncyclical pelvic pain………..……… 89 \nAppendix 2.6: Metaregression to explore heterogeneity in the systematic review on \nprevalence of chronic pelvic pain……………………………………………………. 96 \nAppendix 2.7: Compliance of systematic review on the worldwide prevalence of chronic \npelvic pain with The MOOSE Checklist……………………………………………. 98 \nAppendix 3: Supplementary data for Chapter 3: Systematic review of risk factors in chronic \npelvic pain…………………………………………………………………………… 101 \nAppendix 3.1: Embase search strategy for systematic review on risk factors in chronic pelvic \npain………………………………………………………………………………….. 102 \nAppendix 3.2: Medline search strategy…………………………………………….. 104 \nAppendix 3.3: CPP aetiology systematic review data extraction form…………….. 108 \nAppendix 3.4: List of included studies for the systematic review of risk factors in Chronic \nPelvic Pain………………………………………………………………………….. 113 \nAppendix 3.5: Table of characteristics of studies included in systematic review of risk factors \nin dysmenorrhoea……………………………………………………………………. 124 \nAppendix 3.6: Table of quality assessment of studies on risk factors in dysmenorrhoea…. 162 \nAppendix 3.7: Table of results from studies on risk factors in dysmenorrhoea………. 173 \nAppendix 3.8: Table of characteristics of studies included in systematic review on risk factors \nfor dyspareunia……………………………………………………………………… 199 \nAppendix 3.9: Table of quality assessment of studies on risk factors for dyspareunia… 205 \nAppendix 3.10: Table of results on risk factors for dyspareunia………………………. 210 \nAppendix 3.11: Table of characteristics of studies included in the systematic review with \noutcome as noncyclical pelvic pain………………………………………………… 213 \nAppendix 3.12: Table of quality assessment of included studies on noncyclical pelvic pain\n ………………………………………………………………………………………228 \nAppendix 3.13: Table of results from studies on risk factors in noncyclical pelvic pain… 238 \nAppendix 3.14: Table of Compliance of ‘Factors predisposing women to chronic pelvic pain: \nA Systematic Review’ with The MOOSE Checklist ………………………………………258 \nAppendix 4: No supplementary information for chapter 4…………………………. 260 \nAppendix 5: Supplementary information for chapter 5…………………………….. 261 \nAppendix 5.1: Survey of clinicians’ beliefs on efficacy of LUNA…………………. 262 \nAppendix 6: Supplementary information to Chapter 6: Effectiveness of neuroablation in \nchronic pelvic pain (Dysmenorrhoea): Update of Cochrane Review………………. 272 \n 134\n\n  \nAppendix 6.1: Table of characteristics of studies included in the systematic review on \neffectiveness of neuroablation in dysmenorrhoea…………………………………… 273 \nAppendix 6.2: Results from studies on effectiveness of neuroablation…………….. 281 \nAppendix 6.3: Table of compliance of the neuroablation in dysmenorrhoea: systematic review \nof effectiveness with the QUOROM checklist…………………………….……….. 284 \nAppendix 7: Supplementary information for chapter 7: The LUNA Trial Protocol… 285 \nAppendix 7.1: LUNA Trial patient information sheet………………………………. 286 \nAppendix 7.2: Consent form ………………………………………………………………289 \nAppendix 7.3: Registration and randomisation form…………………………………… 291 \nAppendix 7.4: Post surgery form…………………………………………………… 294 \nAppendix 7.5: Enrolment Questionnaire……………………………………………. 295 \nAppendix 7.6: Follow up questionnaire……………………………………………... 303 \nAppendix 7.7: Investigator agreement……………………………………………… 311 \nAppendix 7.8: Specimen letter to General Practitioner…………………………….  312 \n \n \n 135\n\n  \nLIST OF REFERENCES \n \n \nReference List \n \n 1.  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