Citation
Peripheral and Central Factors in Female Pelvic Pain

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Title:
Peripheral and Central Factors in Female Pelvic Pain
Creator:
Alappattu, Meryl J
Place of Publication:
[Gainesville, Fla.]
Florida
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University of Florida
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english
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1 online resource (74 p.)

Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Rehabilitation Science
Committee Chair:
BISHOP,MARK DONALD
Committee Co-Chair:
GEORGE,STEVEN
Committee Members:
ROBINSON,MIKE E
FILLINGIM,ROGER BENTON
Graduation Date:
5/3/2014

Subjects

Subjects / Keywords:
Fear ( jstor )
Ointments ( jstor )
Pain ( jstor )
Pain sensitivity ( jstor )
Pelvic floor ( jstor )
Pelvic pain ( jstor )
Pelvis ( jstor )
Psychology ( jstor )
Vestibules ( jstor )
Women ( jstor )
Rehabilitation Science -- Dissertations, Academic -- UF
female -- pain -- pelvic
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bibliography ( marcgt )
theses ( marcgt )
government publication (state, provincial, terriorial, dependent) ( marcgt )
born-digital ( sobekcm )
Electronic Thesis or Dissertation
Rehabilitation Science thesis, Ph.D.

Notes

Abstract:
Chronic pelvic pain (CPP) is a non-malignant continuous or recurrent pain of structures related to the pelvis that lasts at least three months and is associated with negative cognitive, behavioral, sexual, and emotional consequences.  Women with pelvic pain exhibit higher pelvic floor muscle pain and pain sensitivity at parts of the body distal from their pelvic region, which may be suggestive of enhanced central nervous system pain processing. The relationship between local and distal pain sensitivity and psychosocial factors in pelvic pain is unclear.  The first purpose of this study is to determine how women with pelvic pain differ from healthy women in response to pain sensitivity testing and in reports of pain-related psychosocial factors to understand the potential influence of these factors on pain and sexual dysfunction.  The second purpose was to determine how an analgesic ointment affected local and remote pains ensitivity in women with pelvic pain. No differences existed in pain sensitivity at local or remote sites in women with pelvic pain compared to healthy women. Women with pelvic pain exhibited greater pain-related psychosocial involvement compared to healthy women. Affective and sensory aspects of painand the presence of sexual dysfunction, in addition to local and remote pain perception, were significantly correlated with intercourse pain.  Results of aim 2 indicated that only pain ratings at the upper and lower vestibule were significantly lower in the lidocaine condition. No significant changes in any other local site or remote sites in response to lidocaine or placebo ointments compared to the natural history condition. This study indicates that a decrease in pain at the local pelvic region does not necessarily affect pain sensitivity at remote body sites. Thus, clinicians who treat pelvic pain should consider using multi-faceted interventions that target central pain mechanisms, such as cognitive behavioral strategies, and interventions aimed at decreasing the local and remote perception of pain. ( en )
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
Source of Description:
Description based on online resource; title from PDF title page.
Source of Description:
This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Thesis:
Thesis (Ph.D.)--University of Florida, 2014.
Local:
Adviser: BISHOP,MARK DONALD.
Local:
Co-adviser: GEORGE,STEVEN.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2015-05-31
Statement of Responsibility:
by Meryl J Alappattu.

Record Information

Source Institution:
UFRGP
Rights Management:
Applicable rights reserved.
Embargo Date:
5/31/2015
Classification:
LD1780 2014 ( lcc )

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1 PERIPHERAL AND CENTRAL FACTORS IN FEMALE PELVIC PAIN By MERYL JOSEPH ALAPPATTU A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOC TOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2014

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2 201 4 Meryl Joseph Alappattu

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3 To Hershey

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4 ACKNOWLEDGMENTS I thank my co investigators and my supervisory committee, with special thanks to my advisor Dr. Mark Bishop, for their direction, guidance, and insight for helping develop and complete this project. I thank my husband for his unconditional love and support during this process. I thank my parents siblings friends and colleagues for their support and encouragement over th ese last four years. Last I thank the women who gave their time to participate in this study.

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5 TABLE OF CONTENTS Page LIST OF TABLES ................................ ................................ ................................ ............ 7 LIST OF FIGURES ................................ ................................ ................................ .......... 8 LIST OF ABBREVIATIONS ................................ ................................ ............................. 9 ABSTRACT ................................ ................................ ................................ ................... 10 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .... 12 Background ................................ ................................ ................................ ............. 12 Psychosocial Influences on Pain ................................ ................................ ............ 13 Maladaptive Nervous System Changes ................................ ................................ .. 14 Ev idence for Pelvic Pain Treatment ................................ ................................ ........ 16 2 SIGNIFICANCE AND SPECIFIC AIMS ................................ ................................ ... 20 Significance ................................ ................................ ................................ ............ 20 Specific Aims ................................ ................................ ................................ .......... 21 Specific Aim 1: To Determine the Associations Among Pain related Psychological Factors, Pain Sensitivity, and Sexual Function in Women with Pelvic Pain Compared to Pain free Women. ................................ .......... 21 Specific Aim 2: To Determine the Extent to Which Analgesia of the Pelvic Floor Muscles Will Affect Local and Remote Pain Sensitivity in Women with Pelvic Pain. ................................ ................................ ............................ 22 3 METHODS ................................ ................................ ................................ .............. 24 Participants and Eligibility Criteria ................................ ................................ ........... 24 Inclus ion Criteria for Healthy Participants ................................ ......................... 24 Inclusion Criteria for Women with Pelvic Pain ................................ .................. 24 Exclusion Criteria ................................ ................................ ............................. 25 Measures of Impairment ................................ ................................ ......................... 25 Pain Sensitivity ................................ ................................ ................................ 25 Pain Intensity and Quality ................................ ................................ ................. 28 Intervention ................................ ................................ ................................ ............. 29 Procedure ................................ ................................ ................................ ......... 29 Randomization and De Briefing of Partic ipants ................................ ................ 30 Measure of Participation Limitation ................................ ................................ ......... 30 Measures of Personal Contextual (Psychological) Factors ................................ ..... 31

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6 Statistical Methods ................................ ................................ ................................ .. 32 Sample Size Estimates ................................ ................................ ........................... 33 4 RESULTS ................................ ................................ ................................ ............... 35 Demographic Information ................................ ................................ ........................ 35 Specific Aim 1: Correlations Between Sexual Dysfunction and Intercourse Pain with Psychosocial Factors and Pain Sensitivity in Women with CPP .................. 35 Pain Intensity and Quality ................................ ................................ ................. 35 Pain Sensitivity ................................ ................................ ................................ 36 Measures of Participation Limitation and Psychosocial Factors ............................. 36 Specific Aim 2: To determine the extent to which analgesia of the pelvic floor muscles will decrease local and remote p ain sensitivity in women with pelvic pain. ................................ ................................ ................................ ..................... 36 Comparison of PPT Ratings at Bilateral Puborectalis Muscles and Upper and Lower Vulvar Vestibule ................................ ................................ ........... 36 Comparison of PPT Ratings at Adductor Longus Tendon ................................ 37 Comparison of PPT Ratings at Tibialis Anterior and Thumb Web .................... 37 Comparison of Ratings of Heat Pain Threshold and Tolerance at Dominant Forearm ................................ ................................ ................................ ......... 38 Comparison of Temporal Summation Magnitude at Glaborous Skin of Dominant Foot ................................ ................................ ............................... 38 Comparison of Bilateral Puborectalis Muscles and Upper and Lower Vulvar Vestibule PPT ................................ ................................ ............................... 38 Comparison of Adductor Longus Tendon PPT ................................ ................. 39 Comparison of Tibialis Anterior and Thumb Web PPT ................................ ..... 39 Comparison of Heat Threshold and Tolerance Temperatures at Dominant Forearm ................................ ................................ ................................ ......... 40 Debriefing session ................................ ................................ ............................ 41 5 DISCUSSION ................................ ................................ ................................ ......... 58 LIST OF REFERENCES ................................ ................................ ............................... 66 BIOGRAPHICAL SKETCH ................................ ................................ ............................ 74

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7 LIST OF TABLES Table page 4 1 Mean baseline pain intensity and quality ................................ ............................ 42 4 2 Mean baseline psychosocial and participation limitation measures .................... 43 4 3 Mean baseline local and remote PPT and pain ratings ................................ ...... 44 4 4 Baseline thermal pain sensitivity and pain ratings ................................ .............. 45 4 5 Correlations of sexual dysfunction and intercourse pain to psycho social measures and pain sensitivity in CPP group ................................ ...................... 46

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8 LIST OF FIGURES Figure page 1 1 Fear Avoidance Model of Pain ................................ ................................ ............ 19 3 1 Study Design Illustration ................................ ................................ ..................... 34 4 1 Right puborectalis PPT ratings ................................ ................................ ........... 48 4 2 Right puborectalis PPT force ................................ ................................ .............. 48 4 3 Left puborectalis PPT ratings ................................ ................................ .............. 49 4 4 Left puborectalis PPT force ................................ ................................ ................ 49 4 5 Upper vestibule PPT ratings ................................ ................................ ............... 50 4 6 Upper vestibule PPT force ................................ ................................ .................. 50 4 7 Lower vestibule PPT ratings ................................ ................................ ............... 51 4 8 Lower vestibule PPT force ................................ ................................ .................. 51 4 9 Bilateral adductor longus tendon PPT ratings ................................ .................... 52 4 10 Bilateral adductor longus tendon PPT force ................................ ....................... 52 4 11 Tibialis anterior PPT ratings ................................ ................................ ................ 53 4 12 Tibialis anterio r PPT force ................................ ................................ .................. 53 4 13 Thumb web PPT ratings ................................ ................................ ..................... 54 4 14 Thumb web PPT force ................................ ................................ ........................ 54 4 15 Forearm heat threshold ratings ................................ ................................ ........... 55 4 16 Forearm heat threshold temperature ................................ ................................ .. 55 4 17 Forearm heat tolerance ratings ................................ ................................ ........... 56 4 18 Forearm heat tolerance temperature ................................ ................................ .. 56 4 19 Dominant foot temporal summation magnitude ................................ .................. 57

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9 LIST OF ABBREVIATIONS FSFI Female Sexual Function Index HTh Heat pain threshold HTol Heat pain tolerance L AL Left adductor longus L PR Left puborectalis muscle LV Lower vestibule MPQ A McGill Pain Questionnaire affective component MPQ S McGill Pain Que stionnaire sensory component NPRS Numerical pain rating scale PASS Pain Anxiety Symptoms Scale PCS Pain Catastrophizing Scale PHQ Patient Health Questionnaire PSEQ Pain Self efficacy Scale PPT Pressure pain threshold R AL Right adductor longus R PR Right puborectalis muscle Sex dys Sexual dysfunction TA Dominant tibialis anterior muscle TS Temporal summation of pain TSK 11 Tampa Scale of Kinesiophobia 11 UV Upper vestibule Web Dominant thumb web

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10 Abstract of Dissertation Presented to the Graduate Scho ol of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy PERIPHERAL AND CENTRAL FACTORS IN FEMALE PELVIC PAIN By Meryl Alappattu May 2014 Chair: Mark Bishop Major: Rehabilitation Science Chronic pelvic pain (CPP) is a non malignant continuous or recurrent pain of structures related to the pelvis that lasts at least three months and is associated with negative cognitive, behavioral, sexual, and emotional consequences. W omen with p elvic pain exhibit higher pelvic floor muscle pain and pain sensitivity at parts of the body distal from their pelvic region, which may be suggestive of enhanced central nervous system pain processing. The relationship between local and distal pain sensiti vity and psychosocial factors in pelvic pain is unclear. The first purpose of this study is to determine how women with pelvic p ain differ from healthy women in response to pain sensitivity testing and in reports of pain related psychosocial factors to un derstand the potential influence of these factors on pain and sexual dysfunction The seco nd purpose was to determine how an analgesic ointment affected local and remote pain sensitivity in women with pelvic pain No differences existed in pain sensitivit y at local or remote sites in women with pelvic pain compared to healthy women Women with pelvic pain exhibited greater pain related psychosocial involvement compared to healthy women. Affective and sensory aspects of pain and the presence of sexual dysfu nction in addition to local and remote pain perception, were significantly correlated with intercourse pain Results of aim 2 indicated that only pain ratings at the upper and

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11 lower vestibule were significantly lower in the lidocaine condition. No signif icant changes in any other local site or remote sites in response to lidocaine or placebo ointments compared to the natural history condition This study indicates that a decrease in pain at the local pelvic region does not necessarily affect pain sensitiv ity at remote body sites. Thus, clinicians who treat pelvic pain should consider using multi faceted interventions that target central pain mechanisms, such as cognitive behavioral strategie s, and interventions aimed at decreasing the local and remote perc eption of pain.

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12 CHAPTER 1 INTRODUCTION Background Chronic pelvic pain (CPP) is a non malignant, continuous or recurrent pain of structures related to the pelvis, lasting at least six months, and often associated with negative cognitive, behavioral, sexual, and emotional consequences. 1 The community prevalence of CPP is estimated at nearly 15% 2 and primary care prevalence estimates are comparable to that of low back pain an d asthma. 3 The economic costs associated with only one type of CPP, endometriosis, is estimated at nearly $22 billion. 4 This 5 The diagnosis and management of CPP is often difficult due to the complexities of causative factors and the interplay of multiple body systems. Women with CPP report feeling depressed, anxious, and sleep disturbances, in addition to limitations in sexual act ivity and mobility. 6 7 The multi factorial etiology of CPP contributes to the challenge of its clinical managem ent. Chronic pelvic pain is associated with dysfunction in one or usually more of the following body systems: gynecological, urological, gastrointestinal, and musculoskeletal. 5 Peripheral supportive structures that contribute to CPP include abdominal and pelvic floor muscles, ligam ents, tendons, fascia, and blood vessels. 8 However, clinical studies indicate that the presence of pathologic changes or lesions in these peripheral systems does not always correlate with complaints of pain. A recent clinical study showed that surgical removal of endometrial lesions does not ne cessarily decrease pelvic pain associated with endometriosis or prevent future endometrial lesions from recurring. 9 Other studies also demonstrate the high recurre nce rate of pain after surgical removal of such lesions. 10 14

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13 Despite some the differences in the etiologies of different pelvic pain medical diagnoses (i.e. end ometriosis, vulvodynia, painful bladder syndrome, and pelvic inflammatory disease, for example), the overlap of clinical elements of women with CPP lements include pain with intercourse (dyspareunia), 15 18 pain during menstruation (dysmenorrhea), 19 20 and reports of myofascial pain of the pelvic floor muscles and proximal soft tissue. 16 21 22 Increasing evidence suggest that pelvic floor muscular dysfunction is associated with CPP. 23 24 A recent study by Montenegro et al. 16 found a significant difference in the prevalence of pelvic floor muscle pain in women with multiple CPP conditions compared to healthy women without pelvic pain. The authors of a 2010 systematic review 21 concluded that myofascial pain of the pelvic floor muscles are associated with a number of CPP conditions that occur in females including, but not limited to, vulvodynia, endometriosis, and interstitial cystitis. Psychosocial Influences on Pain In addition to reports of pain, women wit h CPP exhibit evidence of pain related psychological involvement, including catastrophizing, fear, and hypervigilance during intercourse. These psychological factors comprise the Fear Avoidance Model of Pain (FAM), 25 a conceptual model that theorizes how particular psychological variables may contribute to the maintenance of a musculoskeletal pain condition (Figure 1 1 ). The model was originally introduced to expla in potential psychological causes of chronic LBP, 26 and others have since demonstrated how these psychological variables contribute to the maintenance of pain and disability in people with knee pain, 27 29 ankle pain, 30 and pelvic girdle pain. 31 32 Although the psychologica l factors associated with this model are also relevant to women with pelvic pain. Payne et al. 33 reported that

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14 women with vulvodynia reported more hypervigilance to pain during intercourse (dyspareunia), suggesting that increased attention paid to a threat of potentially painful stimuli during intercourse may int erfere with sexual arousal and diminish the experience of intercourse. Women with vulvodynia also report more catastrophizing thoughts related to intercourse pain compared to non intercourse pain. 34 In a survey of women with IC, 35 a significant number of t hem with CPP complaints reported fear of pain with intercourse compared to healthy controls, in addition to significantly higher reports of dyspareunia. In addition to clinical symptoms, women with CPP also exhibit enhanced pain sensitivity to local and di stal stimuli compared to pain free women. 34 36 39 Collectively, these studies suggest that despite differences in reported etiologies, women with pelvic pain suffer from sexual dysfunction and are influenced by pain related psychological factors that likely exacerbate their pain experience. Maladaptive Nervous System C hanges In addition to clinical symptoms suc h as pain and psychological distress, adaptations in the nervous system contribute to the shift from an acute pain episode to the development of chronic or persistent pain. A peripheral noxious stimulus triggers a series of physiological events that are i ntegrated at various levels of the nervous system and eventually translated into the sensation of pain. 40 Normally, pain is an important warning signal that protects the body from impending danger or damage. Pain becomes pathologic when the response to a stimulus outweighs the magnitude of the stimulus over time. The plasticity of the nervou s and neuromuscular systems contributes to this shift from a single episode of pain to the recurrence of pain or the development of chronic pain. These neuroplastic changes occur in both peripheral and central parts of the nervous system and contribute to enhanced pain sensitivity.

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15 Peripheral sensitization is defined as increased sensitivity of nociceptors as a result of an alteration in transduction at the peripheral terminals. 41 A noxious peripheral stimulus may lead to subsequent enhanced sensitivity i n the periphery. The peripheral hypersensitivity that remains after removal of the stimulus and after resolution of pain is 42 Aley et al. demonstrated that injecting a noxious substance into the paw of a rat resulted in immedi ate primary hyperalgesia in the paw. The rat demonstrated hyperalgesia to noxious stimuli at the paw for up to three weeks after the initial resolution of pain. 43 The results of this study suggest that the peripheral nociceptive stimulation, which resulted in enhanced peripheral pain sensitivity. Neuroplasticity must have occurred for this priming to take place as the excitability of the peripheral terminals increased with one episode of pain. The hypothesized mecha nisms by which this enhanced excitability occurred include the triggering of extracellular ATP receptors that are involved in pain 44 and the increased expression of inflammatory cytokines. 45,46 Peripheral priming is an important concept when considering th e shift from an acute episode of pain to pain recurrence and may play a role in the initiation of central sensitization. In women with CPP, peripheral sensitization may include decreased threshold and tolerance to mechanical stimuli of the pelvic floor an d proximal muscles and ligaments, or an increased response to noxious stimuli in the regions close to the location of pain complaints. 47 Peripheral sensitization may contribute to pelvic floor muscle hyperalgesia in women with CPP. 16,21,48

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16 Central sensitization is defined as the expression of an increase in the excitability of sp inal neurons and is initiated by peripheral sensitization. 49 Although peripheral input is required to initiate central sensitization, it need not be pr esent for central sensitization to be maintained. 50 In people with chronic pain, the enhanced sensitivity of dorsal horn neurons in response to noxious stimuli, i ncluding tissue damage, may lead to plastic changes in the activation of synapses at different levels of the nervous system (spinal cord and supraspinal centers) which are characterized clinically by hypersensitivity of muscles, skin, and viscera. 51 Proxy measures of c entral sensitization in women with pelvic pain may include the presence of hyperalg esia to noxious stimuli at regions of the body distant from the pelvis, such as the foot or hand. Granot et al. 37 applied a series of thermal stimuli to the forearms of women with vulvodyni a and healthy women. The heat pain thresholds of women with vulvodynia were significantly lower than that of healthy women, and suprathreshold pain ratings and anxiety scores were significantly higher for the women with vulvodynia. These results suggest that women with vulvodynia may have enhanced pain sensitivity, perhaps due in part to changes in central nervous system mediated pain processing. Alterations in central nervous system processing are believed to contribute to the maintenance of pain in CP P conditions such as vulvodynia, 37 38 irritable bowel syndrome, 52 and endometriosis 36 and other chronic pain conditions including fibromyalgia 53 54 and low back pain. 55 56 Evidence for Pelvic P ain T reatment Most studies that evaluate treatment effects of interventions for CPP include outcomes for pain and sexual function. 57 61 Commonly used conservative treatments for CPP include EMG biofeedback, manual therapy, and exercise. These studies have some limitations, including the use of non standardized outcome measures, small

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17 sample size, and are limite d to patients of a specific CPP etiology, such as vulvar vestibulitis or interstitial cystitis. In these studies, pain is typically not quantified using standard stimuli at different parts of the body to assess local and remote pain sensitivity despite th e strong evidence for these neuroplastic changes in women with CPP. Additionally, these studies fail to evaluate how interventions for pain affect pain related psychological factors, including catastrophizing, fear, and anxiety, for example. With the exc eption of study performed by Bergeron et al., 59 most studies include treatments directed solely at the pelvic region using techniques such as manual therapy 61 63 and EMG biofeedback. 58 60 The results of these studies indicate that local or pelvic region pain sensitivity may decrease with the use of such interventions However, the impact of locally directed treatments is unclear on central nervous system pain processing, including proxy measures of central sensitization such as remote pain sensitivity and repetitive noxious stimuli Results from other studies have demonstrated that decreasing or blocking peripheral input with analgesic agents in turn decreases the magnitu de of central sensitization proxy measures in other clinical pain conditions. 64 66 These data suggest that targeting peripheral factors or decreasing peripheral dr ive should decrease the extent of or improve central factors such as central sensitization In women with CPP, lidocaine gel is often applied to the internal vaginal mucosa overlying the pelvic floor muscles by clinicians to numb the area in order for wo men to tolerate a pelvic exam or internal manual therapy. Danielsson et al. 67 demonstrated that daily lidocaine use for up to four months significantly reduc ed pain intensity and increased pressure pain thresholds at the vulvar vestibule in women with vulvodynia. Zolnoun and colleagues 68 reported that nightly applic ation of 5% lidocaine for

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18 approximately 7 weeks was associated with improved ability to participate in intercourse and reduced pain intensity in women with vulvar pain T hese studies indicate that lidocaine use may be important in decreasing reports of pa in and pain sensitivity, but they do not address the underlying pain relieving mechanisms of this gel That is, the results of these studies do not indicate if the pain relief that occurred was due solely to changes in the local region of pain or also due to changes in general pain sensitivity measured in remote regions of the body. Understanding how a locally directed treatment influences both local and remote pain would potentially provide information related to how these treatments affect the underlyin g mechanisms of CPP. The use of lidocaine to block peripheral input of the vaginal mucosa overlying the pelvic floor muscles is justified because the manner in which it is applied can be standardized among all participants Also, lidocaine is currently r outinely used by physicians and physical therapists who treat pelvic pain to provide pain relief during pain examinations and/ or treatments. The effects of l ocally directed treatments on central factors such as proxy measures of central sensitization are u nclear in women with CPP The purpose of this study was two fold. The first purpose was to examine how women with CPP compare to pain free women on measures of pain sensitivity, sexual function, and the influence of pain related psychosocial factors. Th e second purpose was to evaluate how a routinely used analgesic ointment affect ed both immediate local and remote pain sensitivity in women with CPP.

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19 Figure 1 1 Fear Avoidance Model of Pain

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20 CHAPTER 2 SIGNIFICANCE AND SPECIFIC AIMS Significance Chronic pelvic pain in females is a prevalent and debilitating condition for which there is no cure. Women with this condition report low satisfaction with intercourse and low levels of sexual desire and arousal, in additio n to sleep disturbances, anxiety, and depression. Two of the most important factors that contribute to the maintenance and the experience of chronic pelvic pain are enhanced pain sensitivity associated with maladaptive changes of the nervous system and th e influence of pain related psychological factors. Women with chronic pelvic pain exhibit higher pain sensitivity to the pelvic floor muscles, external vaginal region, and distal parts of the body compared to healthy women. Women with pelvic pain also fo cus more heavily on their pain during intercourse and other activities and report elevated fear of pain during intercourse. The available literature suggest that reports of pain and sexual dysfunction, pain related psychological factors, and enhanced pain sensitivity magnify the pain experience, but it is not clear how these factors are related to each other. In particular, the influence that enhanced pain sensitivity and psychological factors have on sexual function and self reported pain intensity is un clear. The need for this information is paramount in the practice of clinicians who treat pelvic pain. Understanding the relationship between the presence of pain related psychological factors and sexual dysfunction, for example, may guide clinical deci sion making when determining which interventions to use. Treatments for chronic pelvic pain may include from surgical removal of the vaginal vestibule, EMG biofeedback training to learn relaxation of the pelvic floor muscles, manual therapy of the pelvic f loor muscles, and/or cognitive behavioral

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21 training. These studies often use self reported pain intensity and sexual function as outcome measures, but fail to account for changes in enhanced pain sensitivity and changes in pain related psychological factors such as catastrophizing, pain related fear, and anxiety. Additionally, the interventions used in these studies are not consistent between studies and do not account for variability among the persons applying the interventions. Given the evidence for enh anced local and remote pain sensitivity and psychological factors as potential drivers of the pelvic pain experience, understanding how interventions affect these factors will help to elucidate the mechanisms of how conservative treatments may reduce chron ic pelvic pain. However, a standardized and objective treatment intervention must be used to understand how an intervention influences pain processing in the nervous system. The proposed study will assess how a commonly used analgesic medication for wome n with pelvic pain applied in a standardized manner affects local and remote pain sensitivity in women with chronic pelvic pain. The results of this study will allow us to elucidate how blocking the peripheral input to the mucosa overlying the pelvic floo r muscles affects local and remote pain sensitivity in women with chronic pelvic pain. Specific Aims Specific Aim 1: To Determine the Associations Among Pain related Psychological Factors, Pain Sensitivity, and Sexual Function in Women with Pelvic Pain C ompared to Pain free W omen. Rationale: The Fear Avoidance Model of Musculoskeletal Pain suggests that pain related psychological factors contribute to disability from musculoskeletal pain. Numerous studies have demonstrated the association of catastrophizi ng and pain related fear with disability in patients with chronic and acute musculoskeletal pain conditions, including low back pain, hip and knee osteoarthritis, and foot and ankle

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22 dysfunction. Additionally, considerable evidence supports the presence o f central and peripheral sensitization in women with CPP. This study will examine how psychological factors, pain sensitivity, and sexual function are related in women with pelvic pain. Hypothesis 1.1 : I expect significant positive associations between ne gative pain related psychological factors and pain sensitivity in women with CPP. Additionally I expect significant negative associations between positive pain related cognitions, sexual function and heightened pain sensitivity in women with CPP. Hypothe sis 1.2 : I expect that women with CPP will report significantly higher local and remote pain sensitivity compared to pain free women. I also expect that women with CPP will exhibit significantly higher levels of depression, pain intensity, sexual dysfunct ion, pain with intercourse, pain related psychological involvement (including pain catastrophizing, pain related fear), and significantly lower levels of pain self efficacy compared to pain free women. Specific Aim 2: To Determine the E xtent to W hich Analg esia of the Pelvic F loor Muscles Will Affect Local and Remote Pain Sensitivity in Women with Pelvic P ain. Rationale: Researchers have shown that decreasing peripheral nociceptive input with analgesic medication decreases both peripheral and central measure s of pain in other pain conditions such as irritable bowel syndrome and fibromyalgia. 64 65 69 In women with pelvic pain, lidocaine is used to help tolerate internal manual therapy of the pelvis and for pain with gynecological examinations. Based on previous research in people with irritable bowel syndrome and fi bromyalgia the application of a local analgesic should immediately reduce both local and remote pain sensitivity. This study will examine how lidocaine applied to the pelvic floor will affect local and remote pain sensitivity in women with CPP immediately after its application. Additionally, this study

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23 will examine the effects on local and remote pain sensitivity using a control ointment ( sterile lubricant ) Both ointments (lidocaine and control) were administered with verbal instructions that the ointmen ts were used by health professionals to treat women with pelvic pain. Hypothesis 2.1: I expect that the application of lidocaine to the pelvic floor will reduce both local and remote pain sensitivity immediately after its application in women with CPP to s imilar levels of pain sensitivity of pain free women Hypothesis 2.2: I expect that the application of a control ointment will produce similar changes in local and remote pain sensitivity compared to the application of lidocaine gel.

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24 CHAPTER 3 METHODS Pa rticipants and Eligibility Criteria B oth pain free women and women with CPP were included in this study Both groups of women under went a natural history (NH ) testing session where they completed pain sensitivity testing and self report questionnaires. Wo men with CPP were asked to complete two addi tional sessions where they were randomized to one of two interventional groups: vaginal lidocaine (VL) or vaginal placebo (VP) (Figure 3 1) The World Health Organization (WHO) International Classification of Fu nction (ICF) model was used to categorize the measures used in this study The WHO model classifies function at the level of health condition (the underlying disorder or disease), impairment (measurements at the level of organ systems that assess capabilit ies), activity limitations (the ability to perform a task) and participation restrictions (restriction of participation in societal roles). Inclusion Criteria for Healthy Participants 1. Female, greater than or equal to 18 years old on day of enrollment 2. No c omplaints of pelvic pain 3. Ability to read and understand the Informed Consent Form 4. Ability and willingness to follow all requirements of the study including completion of all self report forms, and participation in psychophysical pain sensitivity testing a nd physical assessments 5. Signed informed consent Inclusion Criteria f or Women with Pelvic Pain 1. Female, greater than or equal to 18 years old on day of enrollment

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25 2. Primary complaint is pelvic pain associated with any one or more of the following diagnoses: C hronic pelvic pain Painful bladder syndrome/interstitial cystitis Vulvodynia Endometriosis Dyspareunia Dysmenorrhea Coccygodynia Irritable bowel syndrome Pelvic inflammatory disease Prior pelvic surgery Mysofascial pain 3. Ability to read and understand the Informed Consent Form 4. Ability and willingness to follow all requirements of the study including completion of all self report forms, and participation in psychophysical pain sensitivity testing and physical assessments 5. Signed informed consent 6. Confirmatio n of inclusion criterion #2 by their referring physician Exclusion Criteria 1. Failure to meet inclusion criteria 2. Physical or medical issues that would have interfere d with study participation including s ensory loss of the hands or feet 3. Pregnant women 4. Women who had never undergone a gynecological pelvic examination 5. Women undergoing physical therapy treatment for pelvic pain Measures of Impairment Pain Sensitivity Quantitative Sensory Testing measures (QST) included both thermal and pressure stimuli. Both pre ssure and thermal measures of pain sensitivity were necessary in this study as differences exist dependent on stimulus modality. Both

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26 thermal and pressure stimuli were tolerance to pain. Additionally, the rmal stimuli were used to evaluate temporal sensory summation of pain. Temporal summation of pain (TSSP) is a dynamic measure of pain processing thought to capture the pain modulation ability of the central nervous system. This is in contrast to static mea sures, such as pain threshold and tolerance, which measure a single moment within the pain processing continuum. Pain sensitivity measures included thermal threshold and tolerance, pressure threshold, temporal sensory summation of pain, and after sensatio ns. Each participant completed a practice session at each testing session to familiarize themselves with the testing procedures and rating their pain. The thermal and pressure testing measures were assessed on the non dominant limbs. After the practice se ssion, the participants completed a baseline testing session consisting of all thermal and pressure measures, followed by a repeat of all testing measures every 15 minutes for one hour. The thermal stimuli measures included pain threshold and tolerance, T SSP and after sensations. All thermal stimuli were administered to the skin of the dominant forearm to prevent local sensitization from practice sessions. All thermal stimuli were delivered with a thermode controlled by the Medoc Neurosensory Analyzer ( TSA 2001; Medoc, Inc, Ramat Yishai, Israel). The delivered temperatures ranged from 35C to 51C. Assessing pain threshold and tolerance, in addition to temporal sensory summation of pain allowed us to evaluate first pain response (primarily a delta noci ceptive fiber mediated) and second pain response (primarily c fiber mediated).

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27 The pressure stimulus measure included pain threshold (PPT) Local pain threshold was assessed at the bilateral internal puborectalis muscles and upper and lower vulvar vestibu le with the use of a thimble algometer 70 Thermal and pressure stimuli were delivered to each participant at the testing periods described above. Participants were assessed using the Numerical Pain Rating Scale (NRPS) The NRPS consists of a scale whose endpoints are designated as '0 = no pain sensation' and '100 = the most intense pain sensation imaginable.' To assess thermal threshold and tolerance, a continuous heat stimulus was began at 35C and was increased at a rate of 0.5C with subjects terminating the stimulus when the temperature reached nsation of heat first c hanged from heat sensation became so strong the participant could no longer stand to have the thermode on their skin ). Threshold and tolerance were measured twice at the baseline and testing i ntervals and the average threshold and tolerance was calculated. To assess TSSP, a train of six heat pulses was applied to the glabrous skin of stimulus interval of 2.5 seconds was used and the temperature of each h eat pulse fluctuated from a baseline of 35C to 48C during each stimulus. The participants were asked to rate the magnitude of their delayed (second) pain sensation following each pulse. This procedure was performed once on the dominant foot at the each testing interval and twice during each practice session on the

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28 non dominant foot. These response ratings are believed to be primarily C fiber mediated. After sensations (AS) are refer to any pain sensations which remain after TSSP induction and the ther mode has been removed After sensations may reflect the intrinsic inhibition properties of the nociceptive system and have been shown to be elevated in other pain conditions, including fibromyalgia and allodynia. To assess AS, pain ratings using the 101 point Numerical Pain Rating Scale for pain were assessed every 15 seconds for up to one minute immediately post TSSP testing. To assess PPT pressure stimuli was delivered with a handheld algometer and/or thimble algometer. Pressure pain threshold was a ssessed at the dominant tibialis anterior muscle belly, bilateral internal pelvic floor muscles, upper and lower vulvar vestibule, and bilateral adductor longus tendons. Pressure pain threshold was measured twice at baseline and at each 15 minute testing interval and the average threshold was calculated. Pain Intensity and Quality Short form McGill Pain Questionnaire (SF MPQ): The SF MPQ is a 20 item index that measures pain in the affective, sensory, and evaluative domains. This valid and reliable 71 72 measure evaluated the quality of the pelvic pain for which the participant was seeking treatment. Numer ical Pain Rating Scale (NPRS): The 101 point NPRS evaluates pain intensity using a scale whose endpoints are designated as '0 = no pain sensation' and '100 = the most intense pain sensation imaginable.' Numerical rating scales are a valid and reliable cl inical measure to assess pain intensity. 73 74

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29 Intervention Procedure All participants completed a natural h istory (NH) session consisting of the self report measures and pain sensitivity testing procedures described above. Women with CPP were asked to complete two additional sessions (a minimum of 3 days and maximum of 5 days between sessions) in which they wer e randomly assigned to one of the following interventions at each of the sessions: vaginal lidocaine (VL) or vaginal placebo (V P ). The practice and baseline pain sensitivity testing at these two sessions was identical to the NH session. To begin each sess ion, baseline pressure pain sensitivity was assessed at the left and right puborectalis muscles six sites on the vulvar vestibule, bilateral adductor longus tendons, and dominant anterior tibialis muscle belly using the measures described above. Baseline t hermal pain sensitivity was assessed at the forearm and foot using the measures described above To begin the intervention portion of each session, the following was stated to each participant: going to apply an ointment commonly used by physicians and physical therapists use to Next, approximately 10 mL of either 2% lidocaine jelly (VL group) or 10 mL of sterile lubricating jelly (V P group) was applied via a syringe to the vaginal mucosa overlying internal pelvic flo The primary investigator who administered the ointments and performed all pain sensitivity testing was blinded to the ointment she applied The following were then assessed every 15 minutes for one hour: pressure pain threshold at the dominant tibialis anterior muscle belly, bilateral adductor longus tendons, right and left puborectalis muscles and upper and lower vulvar vestibule; heat threshold and

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30 tolerance at the dominant forearm; thermal tempor al sensory summation of pain and after sensations at the foot. Randomization and De Briefing of Participants Randomization was performed by an investigator not involved with any of the testing using available on line software ( http://randomizer.org/index/htm ) to generate the randomization schedule. Depending on the randomization schedule, each CPP participant received the lidocaine once and the control ointment one time Post study debriefing: After parti cipants with pelvic pain complete their participation in the study, the investigator who performed the randomization then de brief ed each participant. The debriefing session consisted of asking the participant if she had experienced any more, less, equal, or no pain relief in one session, than another, or if there had been equal pain relief or no pain relief at all compared to the other. The participant was then informed of the session in which she had received the VL and VP. Subsequent to this the particip ant was asked to rate trust of the investigator, ability to control her pain. Each of these ratings was made using a 100mm visual analogue scale. Measure of Participatio n Limitation Female Sexual Function Index (FSFI): The FSFI is a 19 item questionnaire that measures sexual functioning in women in 6 domains: desire, arousal, lubrication, orgasm, satisfaction, and pain. Total scores range from 2 to 36 with scores less t han 26 indicative of sexual dysfunction. The FSFI has demonstrated high internal consistency 0.97) and good test retest reliability (r=0.79 0.90) in women with chronic pelvic pain. 75 77

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31 Measures of Personal Contextual (Psychological) Factors Pain Anxiety Symptoms Scale (PASS): The PASS is a 20 item self report measure that evaluates pain related fear and anxiety in persons with chronic pain d isorders. The PASS 20 contains four subscales: Cogniti ve, Escape/Avoidance, Fear, and Physiological Anxiety. The PASS 20 has high internal consis alpha 0.91) and a stable factorial structure. 78 79 Pain Catastrophizing Scale (PCS): The PCS is a 13 item scale that measures pain catastrophizing in clinical and non clinical populations under thr ee domains: rumination, magnification, and helplessness. The PCS is a reliable and valid measure 80 81 Patient Health Questionnaire (PHQ 9): The PHQ 9 is a 9 item self report measure that evaluates the presence of depressive symptoms. This measure is valid and sensitive and specific to depressive symp toms. 82 Tampa Scale for Kinesiophobia (TSK 11): The TSK 11 is an 11 item self report measure that assesses elevated pain related fear beliefs related to movement o r retest reliability (ICC= 0.81). 83 Patient Centered Outcomes Questionnaire ( PCO): The PCO is a 4 item, 10 point rating scale to assess desires and expectations for treatment outcomes related to pain, fatigue, emotional distress, and interference with daily activities. 84 The original PCO was modified to include items related to limitations in sexual function. Pain Self Efficacy Questionnaire (PSEQ): The PSEQ is a 10 item self report iety of activities, including work,

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32 household duties, and social activities, despite of pain. The PSEQ has high internal retest reliability (r= 0.73). 85 Statistical Methods Statistical analyses were conducted using PASW Statistics for Windows Version 18 (SPSS Inc., Chicago, IL). Alpha was set at the 0.05 level for all analyses. Specific Aim 1: To determine the associations among pain related psychological factors, pain sensitivity and sexual function in women with pelvic pain. 1. Bivariate correlations were calculated among pain related cognitions, pain sensitivity measures, pain intensity, and sexual function using Pearson correlation moments or Spearmans Rho. 2. Separate analyses of variance (ANOVA) were used to test differences between groups on baseline pain sensitivity measures (pain ratings and magnitude of temporal summation of pain) and self report measures. 3. Separate multiple regression models (linear or ordinal) were evaluate d contributions of psychological and pain sensitivity factors to pain and sexual function at the initial testing session In each multiple regression model, demographic variables, pain sensitivity measures, psychological measures with significant bivariate associations with the dependent variable were added to the model. Specific Aim 2: To determine the extent to which ana lgesia of the pelvic floor muscles will decrease local and remote pain sensitivity in women with pelvic pain. Separate repeated measures ANOVAs were conducted for pain intensity ratings with pressure and thermal stimuli at baseline, 15, 30, 45, and 60 minut es post ointment application Time and intervention (NH, V P or V L ) serve d a s the within subjects factors. Separate analyses were performed for pain ratings and forces or temperatures at each location: left and right internal pelvic floor muscles, upper an d lower vulvar vestibule, b ilateral adductor longus tendon dominant tibialis anterior leg, dominant forearm, and foot

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33 Sample Size Estimates Using previously published effect size estimates for visceral pain (effect size= 0.53) and cutaneous pain (effect size= 0.49) following a similar study protocol in patients with irritable bowel syndrome. 69 Using a n alpha of 0.05 and power of 80%, the required sample size to predict changes in visceral pain and cutaneous pain range d from 18 to 22.

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34 Figure 3 1. Study Design I llustration

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35 CHAPTER 4 RESULTS Demographic Information The average age of the pain free group was 29.5 years and the average age of the CPP group wa s 39.57 years (p= 0. 02 ) The average duration of pelvic pain was 60.35 months for the CPP group Twenty seven pain free women and 14 women with CPP were included in the analyses for Aim 1. Nine women with CPP were included in the analyses for Aim 2. Speci fic Aim 1 : Correlations Between Sexual Dysfunction and Intercourse Pain with Psychosocial Factors and Pain Sensitivity in Women with CPP Sexual dysfunction (FSFI scores less than 26 76 ) in the CPP group was significantly positively correlated with age, intercourse pain, and the affective domain of the MPQ. Intercourse pain intensity was significantly positively correlated with both the affective and sensory domains of the MPQ, the presence of sexual dysfunction. Intercourse pain was also significantly correlated with pressure pain ratings at the right puborectalis muscle, lower vestibule, adductor longus, and tibialis anterior. Last, intercourse pain was significantly negatively correlated with right puborectalis muscle PPT (Table 4 5). Pain Intensity a nd Quality As expected, w omen with CPP reported significantly higher current, resting and intercourse pain during the last two and seven days. The worst and least pelvic pain reported by the CPP group during the last two and seven days was also significan tly higher than the pain free group ( Table 4 1) The CPP group reported significantly higher score s on both the sensory and affective domains of the McGill Pain Questionnaire ( Table 4 2 ).

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36 Pain Sensitivity Age was not significantly correlated with any of t he measures of pain sensitivity and therefore not included in any of the models. Women with CPP demonstrated no significant differences in pressure pain threshold at any local or remote sites compared to pain free women. However, women with CPP rated their pain significantly higher at the left puborectalis muscle and the upper vestibule (p=0.03 and 0.02, respectively). No differences existed between groups for any of the thermal measures ( T able 4 4 ) Measures of Participation Limitation and Psychosocial Fa ctors Age was significantly correlated with measures of depression, efficacy and sexual function and included in the comparisons as a covariate. Women with CPP demonstrated significantly higher pain anxiety, depression, catastrophizing, and pain related fe ar compared to pain free women, as well as lower pain self efficacy. The CPP group also scored significantly lower on the FSFI, with the average score for the group on this measure indicative of sexual dysfunction ( Table 4 2). Specific Aim 2 : To determine the extent to which analgesia of the pelvic floor muscles will decrease local and remote pain sensitivity in women with pelvic pain. Comparison of PPT Ratings at Bilateral Puborectalis Muscles and Upper and Lower Vulvar V estibule For right puborectalis pai n ratings results of the ANOVA indicated no significant effects for time ( F ( 1.99 15.95 )=0.5 8 p=0. 68 eta 2 = 0. 07 ), intervention ( F ( 2,16 )=2. 41 p=0. 12 eta 2 = 0. 23 ), or time by intervention interaction ( F ( 2.59 20.71 ) = 1.61 p = 0 .61 eta 2 = 0. 17 ) (Figure 4 1) For left puborectalis pain ratings, the ANOVA indicated no significant effects for time ( F ( 2.00 16.03 ) = 1. 14 p=0.3 4 eta 2 = 0.13), intervention

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37 ( F ( 1.02 8.15 )=3.0 5 p=0.1 1 eta 2 = 0. 28 ) or time by intervention interaction ( F ( 2.51 20.49 )=0. 83 p=0. 48 eta 2 = 0. 09 ) (Figure 4 3 ) The results of the ANOVA for upper vestibule pain ratings indicated a significant effect for intervention ( F ( 2, 16 )= 10.28 p=0.00 1 eta 2 = 0. 56 ) but not for time ( F ( 4, 32 )=2. 21 p=0. 09 eta 2 = 0.2 2 ) or time by intervention interaction ( F ( 3.06,24.50 )=0.6 8 p=0. 71 eta 2 = 0.08) (Figure 4 5 ) Simple contrasts indicated that pain ratings at the upper vestibule were significantly lower for the lidocaine session compared to the NH session (p = 0.01). For lower vestibule pain ratings, the ANOVA ind icated a significant effect for intervention ( F (2,1 6 )=4.3 6 p=0.03, eta 2 = 0.3 5 ) but not for time ( F ( 4, 32 )=1.1 2 p=0.3 7 eta 2 = 0.1 2 ) or time by intervention interaction time ( F ( 2.10,16.78 )=0.28, p=0. 9 7, eta 2 = 0.0 3 ) (Figure 4 7 ) Simple contrasts indicated th at pain ratings at the lower vestibule were significantly lower for the lidocaine session compared to the NH session (p = 0. 03 ). Comparison of PPT Ratings at Adductor L ong us T endon The results of the ANOVA for average adductor longus tendon pain ratings ind icated no significant effect s for time ( F ( 1.97, 15.79 )= 0. 09 p=0. 9 8 eta 2 = 0. 0 1 ) intervention ( F (2,1 6 )= 1.93 p=0.1 8 eta 2 = 0. 19 ), or time by intervention interaction ( F ( 2.76, 22.06 )=1. 56 p=0.1 5 eta 2 = 0.1 6 ) (Figure 4 9 ) Comparison of PPT Ratings at Tibi alis A nterior and Thumb W eb For anterior tibialis pain ratings, the ANOVA indicated no significant effects for time ( F (4, 32 )=0. 63 p=0. 6 4 eta 2 = 0.0 7 ) intervention ( F (2,1 6 )= 2.72 p=0. 10 eta 2 = 0. 25 ), or time by intervention interaction ( F ( 2.11,16.90 )=0.54 p=0.82, eta 2 = 0.0 6 ) (Figure 4 11 ) The ANOVA for thumb web ratings indicated no significant effects for time

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38 ( F ( 1.78,14.23 )=0. 30 p=0.88, eta 2 = 0.04), intervention ( F ( 1.25,10.02 )=0. 87 p=0.4 4 eta 2 = 0.10), or time by intervention interaction ( F ( 2.74,21.9 3 )=0.6 7 p=0.72, eta 2 = 0.08) (Figure 4 13 ) Comparison of Ratings of Heat Pain T hreshold and T olerance at Dominant F orearm Results of the ANOVA for heat threshold indicated no significant effects for time ( F ( 1.78,14.20 )=1.08, p=0.38, eta 2 = 0. 12 ), intervent ion ( F ( 1.05,8.38 )=0.0 3 p=0.96, eta 2 = 0.00 4 ), or time by intervention interaction ( F ( 2.80,22.41 )=1.0 2 p=0.4 3 eta 2 = 0.1 1 ) (Figure 4 15 ) For heat tolerance ratings, the ANOVA revealed a significant effect for time ( F ( 1.83,14.63 )= 4.92 p=0. 003 eta 2 = 0. 38 ) but not for intervention ( F (2,1 6 )=0. 31 p=0. 74 eta 2 = 0. 04 ), or time by intervention interaction ( F ( 2.13,17.07 )=0. 91 p=0. 43 eta 2 = 0. 10 ) (Figure 4 17 ) Simple contrasts indicated that the pain ratings at baseline and 15 minutes were significantly lower c ompared to pain ratings at 60 minutes (p = 0.02 and 0.05, respectively ). Comparison of Temporal Summation Magnitude at Glaborous Skin of Dominant F oot The ANOVA for TS magnitude indicated significant effects for time ( F ( 4,32 )= 2. 98 p=0. 0 3 eta 2 = 0. 27 ) but not for intervention ( F ( 2,16 )= 0. 41 p=0. 67 eta 2 = 0. 0 5 ) or time by intervention interaction ( F ( 3.30,26.41 )=1. 1 1 p=0. 37 eta 2 = 0. 12 ) (Figure 4 19 ) Simple contrasts showed that the magnitude of temporal summation was lower at 45 and 60 minutes compared to baseline (both p=0.03). Comparison of Bilateral Puborectalis Muscles and Upper and Lower Vulvar Vestibule PPT For right puborectalis PPT, results of the ANOVA indicated no significant effects for time ( F ( 4,32 )=0. 50 p=0. 74 eta 2 = 0.06 ), intervention ( F ( 2 ,16 )= 1.38 p=0. 28 eta 2 =

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39 0. 15 ), or time by intervention interaction ( F ( 3.97 31.75 )= 0.78 p=0. 55 eta 2 =0. 09 ) (Figure 4 2 ). For left puborectalis PPT, the ANOVA indicated no significant effects for time ( F ( 4,32 ) =0.76, p=0.48, eta 2 = 0.08), intervention ( F ( 2,16 )=2.74, p=0.10, eta 2 = 0.26) or time by intervention interaction ( F (3.79, 31.80)=0.63, p=0.65, eta 2 = 0.07) (Figure 4 4 ). For upper vestibule PPT, the ANOVA indicated no significant effects for time ( F (4,32) =1.92, p=0.13, eta 2 = 0.19) or intervention ( F (2,16)=3.03, p=0.07, eta 2 = 0.28) but did indicate a significant time by intervention interaction ( F (8,64)=2.64, p=0.02, eta 2 = 0.25 ). Simple contrasts indicated that PPT was significantly higher at 60 minutes compared to baseline in the VL session compared to the NH session (Figure 4 6 ). For lower vestibule PPT, the ANOVA indicated no significant effect s for time ( F (4,32)=1.81 p=0.15, eta 2 = 0.19), intervention ( F (1.13, 9.10)=1.57, p=0.24, eta 2 = 0.16) or time by intervention interaction time ( F (2.46,19.71)=1 .74, p=0.11, eta 2 = 0.18) (Figure 4 8 ). Comparison of Adductor Longus Tendon PPT The results of the ANOVA for average adductor longus tendon PPT indicated no significant effects for time ( F ( 4,32)=1.72 p=0. 17 eta 2 = 0.17 ), intervention ( F (2,16)= 2.40 p=0. 1 2 eta 2 = 0.23 ), or time by intervention interaction ( F ( 8,64 )= 0.73, p=0.67 eta 2 = 0. 08 ) (Figure 4 10 ). Comparison of Tibialis Anterior and Thumb Web PPT For tibialis anterior PPT the ANOVA indicated no significant effects for time ( F (4,32)=0.36, p=0.8 4, e ta 2 = 0.04 ), intervention ( F (2,16)=1.18, p=0.33 eta 2 = 0.13 ), or time by intervention interaction ( F ( 8,64)=0.45, p=0.88 eta 2 = 0.05 ) (Figure 4 12 ).

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40 The ANOVA for thumb web ratings indicated no significant effects for time ( F (4,32)=1.19, p=0.33, eta 2 = 0.13), intervention ( F (2,16)=0.23, p=0.80, eta 2 = 0.03), or time by intervention interaction ( F (3.21,25.70)=0.85, p=0.57, eta 2 = 0.10) (Figure 4 14 ). Comparison of Heat Threshold and Tolerance Temperatures at Dominant Forearm For heat threshold temperature, the AN OVA revealed a significant effect for time ( F (4,32)=21.31, p<0.001, eta 2 = 0.73) and intervention ( F (1.09,8.68)=7.12, p=0.006, eta 2 = 0.47), but not for time by intervention interaction ( F (3.74,29.92)=1.47, p=0.19, eta 2 = 0.16) (Figure 4 1 6 ). Simp le contrasts for time indicated that on average, threshold temperatures at all four time points after baseline testing were significantly lower compared to threshold temperature at baseline ( p=0.004 for 15 min, p<0.001 for the others ). Simple contrasts for interventio n indicated that threshold temperature was significantly higher for the VL and VP session s compared to the NH session (p=0.05 and p=0.003, respectively ). For heat tolerance temperature, the ANOVA revealed a significant effect for time ( F (4,32)=10.02, p<0.0 01, eta 2 = 0.56) and intervention ( F (2,16)=36.46, p<0.001, eta 2 = 0.82), and for time by intervention interaction ( F (8,64)=3.10, p=0.005, eta 2 = 0.28) (Figure 4 1 8 ). Simple contrasts for time indicated that tolerance temperatures at 15 minutes, 30 minutes, 45 minutes, and 60 minutes were significantly higher compared to baseline (p=0.0 3, 0.002, 0.004, and 0.002, respectively). Simple contrasts for intervention indicated that tolerance temperature s were significantly higher for the V P and VL session s compared t o the NH session (p<0.001 and p=0.001, respectively). Simple contrasts for the time by intervention interaction indicated that heat pain tolerance temperature was significantly higher at 30 minutes compared to baseline in the VL and VP sessions compared to the NH Session (both p= 0.04). Also, PPT was

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41 significantly higher at 45 and 60 minutes compared to baseline in the VL session compared to the NH session (p=0.002 and 0.003, respectively) Debriefing session Two of the nine participants who completed the de briefing session reported the y experienced most pain relief during the lidocaine session. Two participants reported no relief with either the lidocaine or placebo and two participants reported equal pain relief. The remaining three reported the most pain r elief during the placebo session. On average, the participants reported their trust of the investigator at 85, their ability to control their pain at 35, and their willingness to participate in studies involving a placebo at 86.

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42 Table 4 1 Mean b aseline pain intensity and quality Pain free (SD) Pelvic pain (SD) P value Current pain 0.00 (0.00) 27.51 (24.58) <0.001 Current pain at rest 0.00 (0.00) 20.00 (22.19) <0.001 Least pain 48 hours 0.00 (0.00) 15.28 (15.65) <0.001 Least pain 7 days 0.1 1 (0.57) 20.36 (28.09) < 0.001 Least pain at rest 48 hours 0.00 (0.00) 1 2.5 0 (14.88) < 0.001 Least pain at rest 7 days 0. 36 (0.36) 9.64 (11.97) <0.001 Worst pain 48 hours 0.00 (0.00) 46.57 (27.26) <0.001 Worst pain 7 days 1.96 (4.58) 55.50 (32.90) <0.001 Worst pain at rest 48 hours 0. 18 (0.94) 28.29 ( 22.46) <0.001 Worst pain at rest 7 days 1.43 (4.35) 45.79 (33.15) <0.001 Intercourse pain 48 hours 0.82 (2.25) 39.86 (36.91) <0.001 Intercourse pain 7 days 1.07 (2.52) 39.9 3 (36.83) <0.001 MPQ S 1.57 (2.10) 16.25 (4.58) <0.001 MPQ A 0.21 (0.63) 3.64 (3.23) <0.001 * Indicates significance at the 0.05 level.

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43 Table 4 2 Mean b aseline psychosocial and participation limitation measures Pain fre e (SD) Pelvic pain (SD) P value PASS 23.43 (17.97) 43.36 (19.58) 0.002 PHQ * 1. 82 (1.74) 8.21 (5.00) <0.001 PSEQ * 51. 92 (12.26) 40.77 (10.92) 0.0 06 PCS 9.21 (9.66) 23.14 (12.40) <0.001 FSFI * 2 7 69 (4.95) 21.16 (6.73) 0.00 1 TSK 11 15.79 (4.10) 23.14 (4.45) <0.001 * Indicates significance at the 0.05 level. * After controlling for age. Age fixed at 32.9 in each covariate model.

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44 Table 4 3. Mean b aseline local and remote PPT and pain ratings Pelvic Pain (SD) Pain free (SD) P value Right pubo rectalis PPT Right puborectalis rating 9.26 (6.06 ) 27.36 (23.53) 11.05 (7.37) 18.57 (18.73) 0.45 0.21 Left puborectalis PPT Left puborectalis rating 5.55 (5.39) 34.96 (26.28) 9.06 (8.19) 17.65 (19.07) 0.16 0.02* Upper vestibule PPT Upper vestibule rating 13.49 (6.09) 25.35 (25.21) 17.70 (8.71) 11.71 (15.09) 0.11 0.03* Lower vestibule PPT Lower vestibule rating 9.59 (6.60) 28.25 (26.11) 11.70 (7.83) 17.88 (18.48) 0.39 0.14 Adductor longus PPT Adductor longus rating 19.42 (5.66) 23.75 (21.07) 23.31 (8.74) 17.39 (17.71) 0.14 0.31 Tibiali s anterior PPT Tibialis anterior rating 53.75 (14.77) 23.71 (16.36) 61.03 (18.72) 16.43 (3.09) 0.21 0.22 Thumb web PPT Thumb web rating 28.96 (8.27) 22.79 (19.74) 35.89 (15.54) 1 6. 13 (17.54) 0.13 0.27 Indicates signific ance at the 0. 05 level.

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45 Table 4 4. Baseline thermal pain sensitivity and pain ratings Pelvic pain (SD) Pain free (SD) P value HTh ( C ) HTh rating 44. 19 (2.16) 30.36 (25.82) 4 3.20 (2.80) 18.23 (21.36) 0.25 0.11 HTol ( C ) HTol rating 47. 06 (1.18) 49.43 (29.21) 47. 81 (1.64) 50.34 (30.29) 0. 13 0.93 TS magnitude 9.36 (10.07) 3 (13.80) 0. 05* Indicates significance at the 0.05 level.

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46 Table 4 5. Correlations of sexual dys function and intercourse pain to psychosocial measures and pain sensitivity in CPP group Sexual dysfunction Intercourse pain Age 0.55* 0.07 Pain duration 0.004 0.16 MPQ S 0.26 0.64* MPQ A 0.55* 0.67* PASS 0.02 0.25 PHQ 0.34 0.16 PSEQ 0.18 0.34 PCS 0 0.13 TSK 0.1 0.07 Sexual dysfunction 1 0.67* Current pain 0.14 0.23 Lea st pain 0.43 0.21 Worst pain 0.47 0.47 Intercourse pain 0.67* 1 R PR PPT 0.51 0.60* R PR Rating 0.29 0.62* L PR PPT 0.18 0.31 L PR Rating 0.08 0.42 UV PPT 0.16 0.18 UV Rating 0.31 0.55 LV PPT 0.2 0.37 LV Rating 0.43 0.60* AL PPT 0.08 0 .36 AL Rating 0.39 0.58* TA PPT 0.08 0.42

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47 Table 4 5. Continued Sexual dysfunction Intercourse pain TA Rating 0.39 0.54* Web PPT 0.35 0.24 Web Rating 0.34 0.53 HTh 0.04 0.2 HTh Rating 0.2 0.4 HTol 0.08 0.01 HTol Rating 0.22 0.36

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48 Figure 4 1. Right puborectalis PPT ratings Figure 4 2. Right puborectalis PPT force

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49 Figure 4 3. Left puborectalis PPT ratings Figure 4 4. Left puborectalis PPT force

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50 Figure 4 5. Upper vestibule PPT ratings Figure 4 6 Up per vestibule PPT force

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51 Figure 4 7. Lower vestibule PPT ratings Figure 4 8. Lower vestibule PPT force

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52 Figure 4 9. Bilateral adductor longus tendon PPT ratings Figure 4 10. Bilateral adductor longus tendon PPT force

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53 Figure 4 11. Tibialis anterior PPT ratings Figure 4 12. Tibialis anterior PPT force

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54 Figure 4 13. Thumb web PPT ratings Figure 4 14. Thumb web PPT force

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55 Figure 4 15. Forearm heat threshold ratings Figure 4 16. Forearm heat threshold temp erature

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56 Figure 4 17. Forearm heat tolerance ratings Figure 4 18. Forearm heat tolerance temperature

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57 Figure 4 19. Dominant foot temporal summation magnitude

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58 CHAPTER 5 DISCUSSION The purposes of the current study were to compare psycho social factors and local and remote pain sensitivity in women with pelvic pain and pain free women and to determine how pain sensitivity was affected in women with pelvic pain after the application of two commonly used ointments to treat pelvic pain The r esults of the first aim of this study demonstrated that women with pelvic pain reported greater pain intensity and greater pain related psychosocial involvement compared to healthy women. The CPP group reported significantly higher least, worst, current, i ntercourse, and resting pelvic pain compared to women without pain in a 48 hour and 7 day period Perhaps the most surprising of these subjective pain ratings was the higher resting pain. Increased nociceptive input associated with activation of the pelvic floor muscles during movement or with noxious pressure to the mucosa overlying these muscles (ie during intercourse) is conceivable in women who report pelvic pain Higher subjective pain while completely at rest may indicate that nociceptive input from t he pelvic region is ongoing in women with pelvic pain and is not always associated with movement or external noxious stimuli in that region. Interestingly, the results of the current study do not fully support our original hypothesis or previous research 36 38 70 that women with pelvic pain would be more sensitive to heat and pressure stimuli compared to healthy women ; that is, we expected women with CPP would have lower thresholds for heat and pressure stimuli However, n o differences existed between groups for the thermal measures or any of the local or remote pressure measures. The differences that did exist be tween groups were the pain ratings at the pelvic floor and vestibule, suggesting that the perception of pain in the

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59 pelvic region was greater for women with CPP even though the magnitude of the stimuli did not differ. This finding lends support to the hypo thesis that women with CPP have greater local pain sensitivity. Our study did not include a design specifically to test sensitivity using standardized stimuli; for example, apply the same pressure to the pelvic floor and vestibule of all participants and a sk them to rate that pressure. Because of this we are unable to make comments regarding hyperalgesia. However, there is some evidence to suggest that women with CPP were more sensitive locally. In addition to subjective pain reports and consistent with pr evious research 38 86 88 women with pelvic pain also exhibited greater pain related psychosocial involvem ent with elevated scores in measures of negative affect The CPP group also reported a decreased pain self efficacy, which is the ability to effectively function in everyday activities despite the presence of pain. The presence of pain related psychosocial factors such as anxiety, pain related fear, and catastrophizing, for example, are well established in women with pelvic pain. The finding of reduced pain self efficacy adds to the previous body of work by suggesting that a woman with CPP has less belief i n her in ability to affect or control pain and the impact of that pain on her function. Thus, the coping abilities of women with pelvic pain may also contribute to their pain experience. The relationship of these psychosocial factors to clinical symptoms of pelvic pain and potential impact on sexual activity, including pain with intercourse and sexual dysfunction is less clear. We originally hypothesized significant positive associations between pain sensitivity, psychosocial factors, and pain with interco urse and our results support this hypothesis Intercourse pain was significantly associated with MPQ

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60 affective and sensory subscales, sexual dysfunction, and PPT ratings at the puborectalis, vulvar vestibule, adductor longus tendons, and tibialis anterior muscle.. Others have reported a lack of a relationship between intercourse pain and pain sensitivity measures. One potential reason for the lack of a relationship with between intercourse pain and pelvic region pain sensitivity and intercourse pain may be the nature of the stimulus. A recent study by Desrochers et al 89 examined the relationship of catastrophizing, hypervigilance, anxiety, pain self efficacy, a nd pain related fear with intercourse compared to induced pain of the vulvar vestibule. Their results indicated that little correlation existed between palpation of the vulvar vestibule and the aforementioned psychosocial variables, to which the authors c ontributed to the relatively non emotional experience of experimentally induced pain versus the highly emotional experience of intercourse. A potential reason for the differences between the current study and the aforementioned study may be the type of sti mulus used in the to assess pelvic region pain sensitivity Digital assessment with a thimble algometer used in the current study may have more closely mirrored sexual activity compared to a cotton swab applied at the vestibule. Though matching the emotion al experience of intercourse may n ot be perfect in an experimental setting future studies should consider using stimuli that better represent painful sexual stimuli Another consideration based on our results is related to treatment interventions for inte rcourse pain. Women with intercourse related pelvic pain may respond to a multi faceted treatment approach that targets pain perception and desensitization of potentially noxious stimuli in the local pelvic region in addition to cognitive based approaches that focus on the affective components of pain. Given the lack of

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61 differences in pressure pain sensitivity at the pelvic region between pain free women with women with pelvic pain treatments for pelvic pain should extend beyond simply treating the pelvic floor, ie through manual therapy or analgesic ointments. Addressing underlying psychosocial factors that may influence the pain experience should be taken in consideration for screening and treatment. If a woman is referred to physical therapy for their pe lvic pain and exhibits strong evidence of pain related psychological distress, such as high catastrophizing, pain related fear, or anxiety for example she may benefit from treatment that includes clinical psychology or sexual counseling prior to or in con junction with the physical therapy. Continual assessment of these psychosocial factors throughout treatment is also necessary particularly if the patient is not improving with only a single mode of treatment The second aim of the study was to compare how lidocaine versus placebo affected local and remote pain sensitivity in women with pelvic pain. Our results showed that t he application of 2% lidocaine reduced pain ratings only at upper and lower vestibule compared to the natural history session. Several p otential explanations exist for the lack of change in pain ratings at other sites in response to th is local intervention Given the presence of pain related psychosocial factors and the associations between local and remote pain perception, intercourse pai n, and sexual dysfunction supported by Aim 1, both local and central factors likely contribute to the pelvic pain experience in women and may need to be considered as potential treatment targets. Solely treating the local pelvic region with an analgesic oi ntment may not be sufficient to reduce the impact of central factors such cognitions or maladaptive behaviors related to pain perception

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62 Another reason for the lack of significant treatment effects in this study may have been the nature of the ointments used. T hough sterile lubricant is used clinically by healthcare providers and patients to decrease pain with contact and/or friction of the vaginal mucosa sterile lubricant does not have analgesic properties that may be effective to reduce pain in women w ith pelvic pain. L idocaine has analgesic properties and is often used by healthcare providers to decrease pain with gynecologic exams or manual therapy of the pelvic floor muscles. We originally hypothesized that the application of lidocaine would change p ain sensitivity (increase thresholds and decrease ratings) over the course of an hour post application and that the placebo ointment and verbal instructional set would reduce pain ratings in a similar manner. However we did not find strong evidence to sup port this hypothesis potentially because the strength of the lidocaine used in the current study may not have been strong enough to effectively block nociceptive input to the vaginal mucosa overlying the pelvic floor muscles in the manner it blocked input to the vulvar vestibule One potential reason for a lack of lidocaine effects in the pelvic floor may be the thickness of the vaginal mucosa relative to the vestibule mucosa and a stronger lidocaine ointment is needed to induce analgesia at the vagina. Ot her studies that have used lidocaine rectally 69 or in the vestibule region 68 for analgesic purposes used 5% strength and results from those studies showed decreases in clinical pain and/or evoked pain ratings. A recent study by Mody et al 90 showed no differences in visual analog scale pain scores among women who received a 1% paracervical block versus no anesthetic prior to an intrauterine device (IUD) insertion. McNicholas et al 91 also showed no differences in cervical pain ratings of women undergoing IUD insertion with use of 2% lidocaine gel compared to

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63 placebo. Collectively, these studies and the results of our current study suggest t hat the lidocaine strength less than 5% may not effectively induce analgesia in the pelvic floor Potentially, future studies examining the effect of a local intervention should use a stronger analgesic (ie 5% or greater lidocaine strength for example) to determine the short term effects on local and remote pain sensitivity. Another potential direction is to examine the frequency at which the lidocaine is applied to the vaginal area. Lidocaine currently is used as a short term analgesic to aid with interve ntional treatments such as pelvic floor muscle massage, internal beam radiation therapy for cancer, and gynecological exams. Zolnoun and colleagues 68 reported a significant decrease in daily pelvic pain and intercourse pain after an average of 7 weeks of nightly application of 5% lidocaine t o the vulvar vestibule in women with vulvar vestibulitis. Potentially, a stronger and more consistent application of an analgesic ointment may help to reduce the perception of pain in the pelvic region. Finally, studies that examine the effects of standardized treatments such as lidocaine compared to or in conjunction with physical and/or cognitive therapies that target underlying pain cognitions or maladaptive behaviors such as intercourse avoidance are also warranted. Last the instructional set used with both the lidocaine and placebo ointment may not have been strongly s uggestive enough of pain relief. The instructional set used in this study prior to lidocaine and placebo application stated that the ointment to be a pplied to the vaginal mucosa was commonly used by physicians and physical therapists to treat women with pelvic pain but did not include any wording suggesting that the ointment was shown to reduce pain. Other studies have shown how using language suggest ive of pain relief prior to performing an intervention can reduce evoked pain. In a study by

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64 Price et al., 92 investigators applied a placebo ointment to the rectum of patients with demonstrated that in the placebo condition significant reduction in evoked p ain ratings occurred over time indicating that the including a strong verbal suggestion of pain relief with an intervention may be important in achieving meaningful reductions in pain Thus, future studies of this nature should include an enhanced instruc tional set that includes a stronger suggestion for pain relief with a placebo intervention. To the best of our knowledge, this study was the first of its kind to directly measure pain sensitivity of the vaginal mucosa overlying the pelvic floor muscles in response to a standard intervention using a vaginal algometer. Use of standard stimuli to assess pain sensitivity has significant advantages in an experimental setting but this device also has clinical implications. For women who report pain with intercour se, gynecological exams, or tampon insertion for example, a vaginal algometer may be useful in determining the efficacy of a particular treatment intervention. In conclusion, the results of the current study demonstrated that women with pelvic pain do not exhibit higher pain sensitivity consistently across multiple local and distal body sites but do exhibit greater involvement of pain related psychosocial factors compared to pain free women and higher perception of pain in the pelvic region The presence o f affective pain factors, in addition to their local and remote perception of pain in the presence of noxious stimuli, is closely linked to intercourse pain. Treatments for pelvic pain should include both a physical component that focuses on decreasing pai n perception in the pelvic region and an affective component that targets decreasing

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65 the influence of pain related psychological factors. The application of 2% lidocaine compared to placebo and natural history resulted only in decreased pain sensitivity at the vulvar vestibule These effects may have been attributed to the strength of the ointment and the relative thickness of the vulvar vestibule mucosa compared to the vaginal mucosa Future studies should examine effects of standard treatments such as ana lgesic ointments compared to physical and/or cognitive therapies that address pain related psychosocial factors. Several limitations exist in the current study. First, there was very large variability of thresholds and ratings in both groups of women. Rat ings of pain ranged from 1 to 80 in healthy women, for example, and 0 to 100 in women with CPP. The small er sample size of the pelvic pain group may have contributed to the high variability in pain ratings but does not account for the variability in health y women A second contributing factor to the high variability may have been the number of practice sessions. Though all participants practiced rating their pain with the thermal and pressure stimuli prior to the baseline and testing intervals, the practice occurred with in the sa me session. Practicing the testing procedures over the several days or sessions may help reduce this variability. Last, the CPP sample in this study included women with a variety of different pelvic pain diagnoses which may or may no t have included pain of the pelvic floor or vestibule, which is where the local pressure stimuli were applied. A more stringent be important for future studies exami ning pelvic floor muscle sensitivity in response to an intervention

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71 62. Montenegro ML, Mateus Vasconcelos EC, Candido dos Reis FJ, Rosa e Silva JC, Nogueira AA, Poli Ne to OB. Thiele massage as a therapeutic option for women with chronic pelvic pain caused by tenderness of pelvic floor muscles. J Eval Clin Pract. Oct 2010;16(5):981 982. 63. Oyama IA, Rejba A, Lukban JC, et al. Modified Thiele massage as therapeutic inter vention for female patients with interstitial cystitis and high tone pelvic floor dysfunction. Urology. Nov 2004;64(5):862 865. 64. Price DD, Zhou Q, Moshiree B, Robinson ME, Verne GN. Peripheral and central contributions to hyperalgesia in irritable bowe l syndrome. J Pain. Aug 2006;7(8):529 535. 65. Staud R, Nagel S, Robinson ME, Price DD. Enhanced central pain processing of fibromyalgia patients is maintained by muscle afferent input: a randomized, double blind, placebo controlled study. Pain. Sep 2009; 145(1 2):96 104. 66. Bishop MD, Beneciuk JM, George SZ. Immediate reduction in temporal sensory summation after thoracic spinal manipulation. Spine J. May 2011;11(5):440 446. 67. Danielsson I, Torstensson T, Brodda Jansen G, Bohm Starke N. EMG biofeedbac k versus topical lidocaine gel: a randomized study for the treatment of women with vulvar vestibulitis. Acta Obstet Gynecol Scand. 2006;85(11):1360 1367. 68. Zolnoun DA, Hartmann KE, Steege JF. Overnight 5% lidocaine ointment for treatment of vulvar vesti bulitis. Obstet Gynecol. Jul 2003;102(1):84 87. 69. Verne GN, Robinson ME, Vase L, Price DD. Reversal of visceral and cutaneous hyperalgesia by local rectal anesthesia in irritable bowel syndrome (IBS) patients. Pain. Sep 2003;105(1 2):223 230. 70. Zolno un D, Bair E, Essick G, Gracely R, Goyal V, Maixner W. Reliability and reproducibility of novel methodology for assessment of pressure pain sensitivity in pelvis. J Pain. Sep 2012;13(9):910 920. 71. Grafton KV, Foster NE, Wright CC. Test retest reliabilit y of the Short Form McGill Pain Questionnaire: assessment of intraclass correlation coefficients and limits of agreement in patients with osteoarthritis. Clin J Pain. Jan Feb 2005;21(1):73 82. 72. Wright KD, Asmundson GJ, McCreary DR. Factorial validity o f the short form McGill pain questionnaire (SF MPQ). Eur J Pain. 2001;5(3):279 284. 73. Jensen MP, Karoly P, Braver S. The measurement of clinical pain intensity: a comparison of six methods. Pain. Oct 1986;27(1):117 126.

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73 87. Kellner R, Slocumb JC, Rosenfeld RC, Pathak D. Fears and beliefs in patients with the pelvic pain syndrome. J Psychosom Res. 1988;32(3):303 310. 88. Payne KA, Binik YM, Amsel R, Khalife S. When sex hurts, anxiety and fear orient attention towards pain. Eur J Pain. Aug 2005;9(4):427 436. 89. Desrochers G, Bergeron S, Khalife S, Dupuis MJ, Jodoin M. Fear avoidance and self efficacy in relation to pain and sexual impairment in women with provoked vestibulodynia. Clin J Pain. Jul Aug 2009;25(6):520 527. 90. Mody SK, Kiley J, Rademaker A, Gawron L, Stika C, Hammond C. Pain control for intraut erine device insertion: a randomized trial of 1% lidocaine paracervical block. Contraception. Dec 2012;86(6):704 709. 91. McNicholas CP, Madden T, Zhao Q, Secura G, Allsworth JE, Peipert JF. Cervical lidocaine for IUD insertional pain: a randomized contro lled trial. Am J Obstet Gynecol. Nov 2012;207(5):384 e381 386. 92. Price DD, Craggs J, Verne GN, Perlstein WM, Robinson ME. Placebo analgesia is accompanied by large reductions in pain related brain activity in irritable bowel syndrome patients. Pain. Jan 2007;127(1 2):63 72.

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74 BIOGRAPHICAL SKETCH Meryl Alappattu received her Bachelor of Science from Indiana Univ ersity in 2005 and her Doctor of Physical Therapy from the University of Florida in 2008. Her clinical expertise as a physical therapist and her research training in musculoskeletal and chronic pain at the University of Florida have provided her the unique opportunity to study the interaction of affective, sensory, and psychological factors that are believed to contribute to chron ic pain condition s in females. She has successfully competed for internal and external doctoral funding from the National Institutes of Health, American Physical Therapy Association, and Foundation for Physical Therapy.


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