1 Vulvodynia: A Common and Under-Recognized Pain Disorder in Women and Female AdolescentsIntegrating Current Knowledge Into Clinical Practice

2 Learning Objectives At the end of this session, learners will be able to: Recognize vulvodynia as a prevalent, misdiagnosed, and under-researched chronic pain disorder affecting millions of women and adolescent girls Define vulvodynia and its subtypes Summarize what is known about the pathophysiology of vulvodynia Identify the infectious, inflammatory, neoplastic and neurologic disorders that need to be ruled out in order to make a diagnosis of vulvodynia Perform a comprehensive exam to diagnose the condition Implement an individualized, multidisciplinary treatment regimen

3 Historical PerspectiveSection #: Title Contents • Contents Historical Perspective Early Descriptions • Current Definition

4 EARLY DESCRIPTIONS OF VULVODYNIA1888 1928 1975 1880 “Hyperaesthesia of the Vulva” Thomas described as “excessive sensibility of the nerves supplying the mucous membrane of some portion of the vulva, sometimes... confined to the vestibule... other times to one labium minus.” What we now refer to as “vulvodynia” was first documented in medical texts in 1880, although some believe that the condition may have been described as far back as the 1st century (McElhiney 2006). Vulvodynia was described as “supersensitiveness of the vulva” and “a fruitful source of dyspareunia,” before mention of the condition disappeared from medical texts for 5 decades. Thomas 1880 Historical Perspective

5 EARLY DESCRIPTIONS OF VULVODYNIA1880 1928 1975 1888 “Supersensitiveness of the Vulva” Skene: “This disease...is characterized by the supersensitiveness of the vulva...No redness or other external manifestation of the disease is visible...When the examining finger comes in contact with the hyperaesthetic part, the patient complains of pain, which is sometimes so great as to cause her to cry out. Sexual intercourse is equally painful and becomes, in aggravated cases, impossible.” Skene 1888 Historical Perspective

6 EARLY DESCRIPTIONS OF VULVODYNIA 1975 1928 “Sensitive Deep Red Spots” Kelly described “exquisitely sensitive deep- red spots in the mucosa of the hymenal ring as a fruitful source of dyspareunia.” Kelly 1928 Historical Perspective

7 EARLY DESCRIPTIONS OF VULVODYNIA 1928 1975 No mention of the condition in medical texts for 5 decades. Historical Perspective

8 EARLY DESCRIPTIONS OF VULVODYNIA 1928 1975 “Burning Vulva Syndrome” Vulvodynia is defined as burning vulva syndrome by the International Society for the Study of Vulvovaginal Disease (ISSVD) at 1975 World Congress. McKay 1984, Moyal-Barracco 2004, Haefner 2007 Historical Perspective

9 The current ISSVD definition of vulvodynia is:CURRENT DEFINITION The current ISSVD definition of vulvodynia is: Vulvar pain of at least 3 months duration, without a clear identifiable cause, which may have potential associated factors. Diagnosis of exclusion Idiopathic pain disorder Bornstein 2016 Historical Perspective

10 Magnitude of the ProblemPrevalence • Incidence • Remission Misdiagnosis • Economic impact • Quality of life

11 PREVALENCE & INCIDENCEVulvodynia has been documented in preadolescent girls (Reed 2008). A study of adolescent girls aged suggests that the condition is quite prevalent among young women (Landry 2009). Incidence Annual incidence is 3.1% in one study (Reed 2012). More recently, the incidence was 4.2 cases per 100 woman- years and differed by age, ethnicity and marital status (Reed 2014). Prevalence Four independent NIH-funded population-based studies, three of which included a clinical confirmation component, demonstrate a point prevalence of 3-7% in reproductive-aged women (Harlow 2003, Arnold 2007, Reed 2004, Reed 2006). Approximately 7% of American women will have symptoms consistent with vulvodynia by age 40, which significantly differ by ethnicity (Harlow 2014). Magnitude of the Problem

12 REMISSION RATES Remission History of any remission ranges from 26 to 38%, depending on duration of pain (Nguyen 2015). In other population-based studies, remission ranged from 17-25%, with a rate of remission incidence of 22% over two years (Reed/Haefner 2008, Reed 2012). Magnitude of the Problem

13 AFFECTED POPULATIONS Affected Populations All ages affected, although the incidence of symptom onset appears highest between ages 18 to 25 (Harlow 2003, Reed 2012, Harlow 2014) All ethnicities affected, although Hispanic women have an increased risk (Harlow 2003, Reed 2012, Harlow 2014, Reed 2014) and different subtypes (Nguyen 2015). Studies of women found that the incidence of symptom onset is highest between the ages of 18 and 25. Once thought to affect primarily white women, recent studies indicate that Hispanic women are significantly more likely to develop vulvodynia, and may present with different vulvar pain subtypes. Magnitude of the Problem

14 MISDIAGNOSIS & ECONOMIC IMPACTMisdiagnosis is Common 2003: First NIH-funded population-based study (Harlow 2003) • 60% of women consulted at least 3 doctors in seeking a diagnosis; 40% of them remained undiagnosed after 3 medical consultations. 2012: Recent NIH-funded population-based study (Reed 2012) • Only 1.4% of women seeking medical care were accurately diagnosed. Because vulvodynia is rarely covered in medical school curricula and residency programs, symptoms mimic those of common vulvovaginal infections, and in many cases, no abnormalities of the vulvar tissue can be seen upon examination, women are often misdiagnosed. In 2003, the first federally funded population-based epidemiologic study in Boston found that almost 60% of patients reported visiting three or more health care providers to receive a diagnosis, 40% of whom remained undiagnosed after 3 consultations. Using prevalence estimates of three to seven percent, Xie and colleagues demonstrated the significant economic impact of vulvodynia in the U.S. of $31 to $72 billion in direct and indirect costs. Significant Economic Impact US direct/indirect cost is $31-$72 billion (Xie 2012). Magnitude of the Problem

15 QUALITY OF LIFE This graphic summarizes common themes experienced by women with vulvodynia and their interrelation (Donaldson 2010). Living with vulvodynia often limits certain activities of daily living, such as sitting for extended periods, and engaging in sexual intercourse and physical exercise. In severe cases, women have to resign from their jobs and apply for disability. Confusion About Onset of Pain Deleterious Consequences on Physical, Emotional and Sexual Health and Relationships Fruitless Search for Causal Attributions Several studies summarize the negative biopsychosocial outcomes, personal distress and sexual dysfunction reported by vulvodynia sufferers. Self-Management Attempts with Various Strategies Provide Little Relief Delay in Treatment for Serious Health Condition Numerous Barriers to Seeking Medical Care and Help Magnitude of the Problem

16 QUALITY OF LIFE Xie found that women with vulvodynia report lower quality of life scores than kidney transplant recipients and those with prior osteoporosis-related fractures (Xie 2012). Newly diagnosed women report substantial impact of vulvar pain on their lives, and little control over their symptoms (Piper 2012). Among women of reproductive age, Johnson found that barriers to consistent health carefrequently experienced in early adulthood contributed to not finding successful medical management (Johnson 2015). However, those who became pregnant reported finding a personally acceptable level of pain (Johnson 2015). Stigma and isolation are common. Only 1 in 4 women report feeling comfortable discussing the condition with women friends (Nguyen/ MacLehose 2012). They also report an increase in feelings of invalidation and isolation when they have co-existing pain disorders (Nguyen/Ecklund 2012). Magnitude of the Problem

17 Anatomy and Neurobiology of the Urogenital TractVulva and Vulvar Vestibule • Innervation of the Vulva Pelvic Floor Musculature

21 Terminology and ClassificationISSVD Classification: Vulvar Pain and Vulvodynia Other Terms

22 ISSVD CLASSIFICATION: VULVAR PAINVulvar pain related to a specific disorder, i.e., NOT vulvodynia Infectious (recurrent candidiasis, herpes) Inflammatory (lichen sclerosus, lichen planus, immunobullous disorders) Neoplastic (Paget’s disease, squamous cell carcinoma) Neurologic (post-herpetic neuralgia, nerve compression or injury, neuroma) Trauma (female genital cutting, obstetrical) Iatrogenic (post-operative, chemotherapy, radiation) Hormonal deficiencies (genito-urinary syndrome of menopause, lactational amenorrhea) The current classification differentiates: vulvar pain due to a known cause vs. idiopathic chronic vulvar pain (ie, vulvodynia). Bornstein 2016 Terminology and Classification

23 ISSVD CLASSIFICATION: VULVODYNIAVulvodynia is vulvar pain of at least 3 months duration, without a clear identifiable cause, which may have potential associated factors*. Descriptors: Generalized (multiple areas of the vulva involved), localized (one area of the vulva involved, e.g., clitorodynia, hemi-vulvodynia) or mixed (localized and generalized) Provoked (insertional, contact), spontaneous or mixed (provoked and spontaneous) - Provoked pain local to the vestibule: “provoked vestibulodynia” (previously vulvar vestibulitis syndrome) Onset (primary or secondary) Temporal pattern (intermittent, persistent, constant, immediate, or delayed) Pain is first classified by location , ie, generalized (several areas of the vulva), localized (a specific area of the vulva) or mixed; secondly, it is classified by provocation (provoked, spontaneous or mixed). It is also described by onset (either primary or secondary) and temporal pattern (intermittent, persistent, constant, immediate, or delayed). The 2 most common forms of vulvodynia are: generalized vulvodynia and provoked vestibulodynia (formerly vulvar vestibulitis syndrome). It should be noted that women may have both a specific disorder (eg, lichen sclerosus) and vulvodynia. Please see Slide 26 for potential associated factors. Terminology and Classification

24 OTHER TERMS - CONFUSION IS COMMONGeneralized Provoked Vulvodynia Vestibulodynia Hyperaesthesia of the vulva Dysesthetic Vulvodynia Vulvar Dysesthesia Essential Vulvodynia Vulvar Vestibulitis Syndrome Vestibular Adenitis Minor Vestibular Gland Syndrome Localized Provoked Vulvodynia Since 1975, many terms have been used to describe the 2 most common vulvodynia subtypes, causing confusion among the medical, scientific and patient communities. Terminology and Classification

25 Pathophysiology Potential Factors Associated with Vulvodynia • Pain Transmission Neuroproliferation • Mast Cells

26 POTENTIAL FACTORS ASSOCIATED WITH VULVODYNIALevel of Evidence Potential Factor* Co-morbidities and other pain syndromes (eg, painful bladder syndrome, fibromyalgia, irritable bowel syndrome, temporomandibular disorder) 2a Genetics 2b Hormonal factors (eg, pharmacologically induced) Inflammation Musculoskeletal (eg, pelvic muscle overactivity, myofascial, biomechanical) Neurologic mechanisms: central (spine, brain) and peripheral Neuroproliferation Psychosocial factors (eg, mood, interpersonal, coping, role, sexual function) Structural defects (eg, perineal descent) The pathophysiology of vulvodynia remains inconclusive. (See vulvodynia pathophysiology references 1-50.) However, research to date supports the theory that multiple mechanisms predispose, trigger, and perpetuate symptoms. Co-morbidities: painful bladder syndrome, fibromyalgia, irritable bowel syndrome, and temporomandibular disorder are significantly associated with vulvodynia Genetics: Some women with vulvodynia have a genetic predisposition that increases the risk of candidiasis or other infections, prolongs inflammatory responses or affects their response to oral contraceptives Hormonal factors: In some women, the use of combined hormonal contraceptives has been associated with an increased risk of vulvodynia Inflammation: Based on either histologic, immunologic or biochemical studies, inflammation has been associated with vulvodynia. There is an increase in the number of mast cells and degranulated mast cells Musculoskeletal: Pelvic floor overactivity is frequent Neurologic mechanisms: Higher sensitivity to stimulation in non-genital areas is seen and brain imaging studies depict function changes Neuroproliferation: Increase in the density of nerve endings in the vestibule (ie, nociceptors with increased density of the vanilloid receptor VR1) leading to increased sensitivity Psychosocial factors: Anxiety, depression, childhood victimization, posttraumatic stress, and mood or anxiety disorder Structural defects: There are reports that repair of pelvic floor prolapse is associated with the resolution of vulvodynia Bornstein 2016 *The factors are ranked by alphabetical order. Pathophysiology

27 NORMAL PAIN TRANSMISSION VSNORMAL PAIN TRANSMISSION VS. PROPOSED MECHANISMS OF ALTERED PAIN TRANSMISSION IN VULVODYNIA Our understanding of the pathophysiologic mechanisms of vulvodynia is in its infancy. This diagram compares the mechanisms of normal pain transmission to the proposed pathophysiologic transmission of pain in women with vulvodynia. It is likely that different mechanisms, influenced by several predisposing, triggering, and maintaining factors, as well as genetic and environmental factors, will be identified. Pathophysiology

28 NEUROPROLIFERATION One possible pathophysiologic mechanism of vestibulodynia is neuroproliferation (Bornstein 1997, Bornstein 2008). Subepithelial and intraepithelial nerve fibers have been detected in patients with vestibulodynia. Branching of the nerve fibers within the epithelium is rarely seen. One possible pathophysiologic mechanism of vestibulodynia is neuroproliferation. A special nerve fiber staining, PGP 9.5, was used to depict small nerve fibers in patients with vestibulodynia and women without vestibulodynia undergoing vestibular biopsy for other conditions. Subepithelial and intraepithelial nerve fibers were detected only in patients with vestibulodynia. The fibers penetrated the basal membrane and continued vertically for more than half the distance to the epithelial surface. Branching of the nerve fibers within the epithelium was rarely seen (Bornstein 1997, Bornstein 2008). Pathophysiology

29 MAST CELLS In vestibulodynia, there is frequently an increase in mast cell number and activity. Mast cells show degranulation. The discharged granules contain tryptase, histamine, serotonin, bradykinin, heparanase, nerve growth factor, etc. Some of these enzymes may participate in the pathogenesis of vestibulodynia (Bornstein 2004). In vestibulodynia, there is frequently an increase in mast cell number and activity. In Bornstein et al, mast cells, stained by Giemsa, showed degranulation. The discharged granules contained tryptase, histamine, serotonin, bradykinin, heparanase, nerve growth factor, etc. Some of these enzymes may participate in the pathogenesis of vestibulodynia (Bornstein 2004). Pathophysiology

30 Differential DiagnosisDisorders known to cause vulvar pain (rule-out diagnoses) vs. Vulvodynia

31 POSSIBLE RISK FACTORS FOR VULVODYNIAPostulated risk factors reported in the literature to date: Vulvovaginal infection Oral contraceptive use Genetic variability Dysmenorrhea, chronic pain in other areas of the body Autoimmune disease, altered immuno- inflammatory response Allergies, vulvar dermatologic disorders Early age of first intercourse, pain with first intercourse, pain with/after sex Early menarche Nulliparity Childhood enuresis, nocturnal urination, Urinary burning, pain with wiping Pain with bike riding Difficulty or severe pain with first tampon use Adverse life experiences Preliminary findings of research on factors associated with the risk of developing vulvodynia indicate that there may be multiple risk factors involved, but larger studies are needed to confirm these findings. Multiple studies suggest that vulvodynia patients experience more frequent vaginal infections; however, in most cases, prior vaginal infections were either self-reported or unconfirmed by the treating clinician. Research demonstrates that patients and clinicians are poor at accurately diagnosing vaginal infections (Ferris 1996, Ferris 2002, Ledger 2004, Schwiertz 2006). The only population-based case-control study to date that compared the frequency of self-reported urogenital infections before the onset of vulvar pain demonstrated that a history of genital warts (OR 3.4), trichomoniasis (OR 5.7), urinary tract infection (OR 2.0), or yeast infection (OR 2.1) was associated with increased risk of vulvodynia. The researchers also found that women with multiple infections prior to the onset of vulvar pain were at highest risk; a combination of urinary tract infection and sexually transmitted infections (STIs) was associated with a 10-fold higher risk (Nguyen 2009). Recent pathophysiologic studies have demonstrated a relationship between vulvodynia and Candida albicans (Babula 2004, Foster 2007, Ramirez De Knott 2005, Farmer 2011).  Research to date appears to implicate oral contraceptive (OC) use in the development and/or maintenance of vulvodynia in some subgroups. Some clinicians propose that the use of OCs, particularly at an early age, down-regulates estrogen receptors in the vulvovaginal tissue, causing the vestibular epithelium to become thin and fragile. In a study of women using Yasmin, Battaglia (2012) found decreased labial thickness, introital area, frequency of intercourse and orgasm during intercourse, as well as increased pain with intercourse and pulsatility index of the dorsal clitoral and posterior labial arteries. In another study, quantitative sensory testing of the vestibular mucosa in healthy women revealed significantly lower mechanical pain thresholds in the OC group, with the most sensitivity in the posterior vestibule. The investigators concluded that OCs may induce increased sensitivity in the vestibular mucosa in healthy women, possibly contributing to the development of vulvodynia (Bohm-Starke 2004). Heddini (2012) found that provoked vestibulodynia patients carrying a polymorphism in the guanosine triphosphate cyclohydrolase (GCH1) gene and using OCs had higher pain sensitivity compared to non-carriers. Several studies have demonstrated increased risk in this patient population (Sjoberg 1997, Greenstein 2007, Bazin 1994, Bouchard 2002), although a population-based study did not (Harlow 2008). Other risk factors reported in the literature include a history of allergies (Harlow 2009); vulvar dermatoses (Coombs 2011); autoimmune disease (Driul 2011) and an altered immuno-inflammatory response (Breshears 2011); early age of menarche (Harlow 2001); dysmenorrhea (Granot 2004); difficulty or severe pain with first tampon use (Harlow 2003, Landry 2009, Legocki 2011); early age of first intercourse (Bazin 1994, Berglund 2002); pain with first intercourse (Legocki 2011); pain with/after sex (Reed 2012); nulliparity (Edgardh 2007); childhood nocturnal enuresis (Greenstein 2005); urinary burning (Reed 2012); nocturnal urination, pain with wiping, and bike riding (Legocki 2011); genetic variability (Babula 2008, Foster 2004, Gerber 2003, Jeremias 2000, Lev-Sagie 2009) and altered gene expression, particularly in genes implicated in osteoarthritis (Breshears 2011) and with an altered immuno-inflammatory response (Bornstein 2004, Bornstein 2008, Foster 1997, Foster 2007, Gerber 2002, Harlow 2009, Lev-Sagie 2009); and chronic pain in other areas of the body (Falik-Zaccai 2011, Arnold 2006, Heddini 2012). (See differential diagnosis references.) Although one study supports some degree of association (Harlow 2005), several studies have refuted the notion that prior sexual and/or physical abuse is a risk factor for vulvodynia (Dalton 2002, Plante 2008, Edwards 1997, Reed 2000). Khandker (2011) is the only population-based epidemiological study to demonstrate antecedent depression and anxiety as risk factors for vulvodynia. Plante (2008) demonstrated that women with vulvodynia reported more adverse life experiences. See Bohm-Starke 2010 for additional information. Differential Diagnosis

32 RULE-OUT DIAGNOSES CHRONIC VULVAR PAINVisible and/or neurologic findings No visible findings except possible erythema. Hyperalgesia (painful stimuli induce sensitivity). Allodynia (non-painful stimuli induces pain). Pain can be: primary or secondary; spontaneous or provoked; intermittent, persistent, constant, immediate, delayed According to the International Society for the Study of Vulvovaginal Disease (ISSVD) (Bornstein 2016), known causes of chronic vulvar pain are: (1) infectious, (2) inflammatory, (3) neoplastic, (4) traumatic, (5) iatrogenic, (6) hormonal deficiencies, or (7) neurologic. If the cause is unknown, it is classified as vulvodynia. Conditions falling into the first 7 categories must be ruled out prior to making a diagnosis of vulvodynia. Examples of some of these prevalent conditions follow, with references to journal articles that provide information on diagnosis and treatment since this is beyond the scope of the current program. Infectious, inflammatory, neoplastic, neurologic, traumatic, iatrogenic, hormonal deficiencies (treat accordingly) Pain is localized to one part of the vulva (vestibule, clitoris, labia, etc.) Pain throughout the entire vulva though some parts may be more painful than others. Provocation typically exacerbates symptoms. Pain may be described as burning, stabbing, stinging, etc. Generalized Vulvodynia Clitorodynia - pain confined to the clitoris. Can be described as burning or stabbing pain or less commonly persistent arousal (AKA persistent genital arousal disorder - PGAD). Vestibulodynia (AKA vulvar vestibulitis (VVS) or provoked vestibulodynia (PVD). Primary if pain began at first vaginal penetration attempt. Secondary if pain began after a period of pain-free vaginal penetration. Haefner 2007, Bornstein 2016 Differential Diagnosis

39 RULE-OUT DIAGNOSES NEUROLOGIC DISORDERSPudendal, Genitofemoral and/or Ilioinguinal Nerve Injury Can be caused by several different insults including: childbirth, sports injuries, trauma and surgery (for incontinence or for vaginal vault prolapse) (see Paulson 2011, Masata 2012, Parnell 2012, Bekker 2012) Differential Diagnosis

40 RULE-OUT DIAGNOSES NEUROLOGIC DISORDERSPudendal Neuralgia due to Nerve Entrapment* (see Peng 2009, Insola 2010) Diagnosed by presence of all five Nantes Criteria: 1) pain in the anatomical territory of the pudendal nerve, 2) worse on sitting, 3) not usually waking the patient at night, 4) not accompanied by any objective perineal sensory loss, with 5) a positive anesthetic block of the pudendal nerve at the ischial spine (Labat 2010) Patients often present with associated urinary, anorectal, sexual, neuromuscular, and hypersensitization signs, which can complicate the diagnostic approach and therapeutic management (Labat 2010). *These disorders are many times also diagnoses of exclusion, and can, therefore, be difficult to definitively differentiate from vulvodynia. Differential Diagnosis

41 RULE-OUT DIAGNOSES NEUROLOGIC DISORDERSPeripheral Neuropathy/Neuralgia* Neuropathy induced by diabetes, chemotherapy, multiple sclerosis (see Stavraka 2012, Loprinzi 2008) Herpes zoster virus can lead to post-herpetic neuralgia masking as vulvodynia (see Oaklander 2002). Pharmacologic toxicity, eg, nitrofurantoin (see Tan 2012) *These disorders are many times also diagnoses of exclusion, and can, therefore, be difficult to definitively differentiate from vulvodynia. Differential Diagnosis

42 RULE-OUT DIAGNOSES NEUROLOGIC (AND OTHER) DISORDERSSacral Meningeal (Tarlov) Cysts (see Hiers 2010, Van de Kleft 1991) Referred pain from ruptured disc or scarring around sacral nerve roots after disc surgery, pelvic floor muscle dysfunction and/or orthopedic condition, e.g., labral hip tear (image below) The MRI on the left shows a Tarlov cyst, a cerebrospinal fluid (CSF)-filled sac located in the spinal canal at the S1-S4 region of the spinal cord. Patients with Tarlov cysts are usually asymptomatic, but some do experience radiating pelvic and urogenital pain, persistent genital arousal disorder (PGAD), sexual dysfunction, and bladder dysfunction, among other symptoms. The image on the right shows a labral hip tear, which can refer pain to the urogenital region. Image courtesy of Wikimedia Commons Image courtesy of Deborah Coady Differential Diagnosis

43 RULE-OUT DIAGNOSES TRAUMATrauma to the vulva may lead to chronic vulvar pain. Female genital cutting Perineal trauma Straddle injuries Bicycles Falls from climbing Injuries to pelvis Motor vehicle accidents More than 130 million women across the world have undergone female genital cutting (FGC) and in some countries prevalence of FGC is greater than 85% (UNICEF 2014). Perineal trauma from a poorly healed or poorly repaired laceration or episiotomy may cause chronic vulvar pain or recurrent tearing (and pain) during intercourse. A recent review showed that 12.8% of women experience chronic vulvar pain at least 5 months after episiotomy (Turmo 2015). Lastly, straddle injuries (most commonly from bicycles or falls from climbing) or injuries to the pelvis from motor vehicle accidents are uncommonly the cause of persistent vulvar pain. Differential Diagnosis

46 VULVODYNIA ASSESSMENTCHRONIC VULVAR PAIN Visible and/or neurologic findings No visible findings except possible erythema. Hyperalgesia. Allodynia. Pain can be: primary or secondary; spontaneous or provoked; intermittent, persistent, constant, immediate, delayed After visible and/or neurologic causes of vulvar pain are identified and treated, one moves on to evaluate the patient for vulvodynia. Hyperalgesia and allodynia are present, with or without the presence of erythema. Although women with vulvodynia describe their pain in a variety of ways (eg, stabbing, aching, raw, searing, sharp, throbbing, knife-like, etc), burning is most commonly reported. If the pain is localized to the vulvar vestibule and provoked, the diagnosis is likely to be provoked vestibulodynia (PVD). PVD is further categorized as primary or secondary. PVD is the most common subtype affecting 80% of women with chronic vulvar pain symptoms (Harlow 2003). If the pain is generalized to multiple areas of the vulva and spontaneous, but exacerbated by touch/pressure, the diagnosis is likely generalized vulvodynia. Twenty percent of women suffer from this subtype or a mixture of both (Reed 2003, Edwards 2004). Infectious, inflammatory, neoplastic, neurologic, trauma,iatrogenic, hormonal deficiencies (treat accordingly) Pain is localized to one part of the vulva (vestibule, clitoris, labia, etc.) Pain throughout the entire vulva though some parts may be more painful than others. Provocation typically exacerbates symptoms. Pain may be described as burning, stabbing, stinging, etc. Generalized vulvodynia Clitorodynia - pain confined to the clitoris. Can be described as burning or stabbing pain or less commonly persistent arousal (also know as persistent genital arousal disorder - PGAD). Vestibulodynia (aka vulvar vestibulitis or provoked vestibulodynia (PVD)). Primary if pain began at first vaginal penetration attempt. Secondary if pain began after a period of pain-free vaginal penetration. Haefner 2007, Bornstein 2016 Differential Diagnosis

47 VULVODYNIA ASSESSMENT SCREENING QUESTIONSFour Questions Highly Predictive of a Clinical Diagnosis Experience genital “pain”? Experience genital burning > 3 months? 10 or more episodes of pain on contact with tampon insertion, sexual intercourse or gynecological exam? Does pain on contact limit/prevent intercourse? Based on data from a National Institutes of Health (NIH)-funded population-based study, these 4 questions have been found to be highly predictive of an office-based diagnosis of vulvodynia (Harlow 2009). These questions were validated against clinical examination with 80% specificity and 95% sensitivity. They should be included on screening forms to help healthcare practitioners identify women and adolescents who may be suffering from the condition. Harlow 2009 Differential Diagnosis

48 2015 ISSVD, ISSWSH, IPPS CONSENSUS TERMINOLOGY AND CLASSIFICATION OF VULVODYNIAVulvodynia is vulvar pain of at least 3 months duration, without a clear identifiable cause, which may have potential associated factors. Descriptors: Localized (e.g., vestibulodynia, clitorodynia), generalized or mixed (localized and generalized) Provoked (eg, insertional, contact), spontaneous or mixed (provoked and spontaneous) Onset (primary or secondary) Temporal pattern (intermittent, persistent, constant, immediate, delayed) For more than a decade, gynecologists, dermatologists, vulvar pain specialists, and researchers have used the 2003 ISSVD terminology as a guide to diagnosing vulvar pain. This terminology evolved over years of discussion on the nature of idiopathic vulvar pain, especially that occurring during sexual activity and vaginal penetration. The 2003 terminology divided vulvar pain into 2 overarching categories: vulvar pain related to a specific disorder and vulvodynia, defined specifically as “vulvar discomfort, most often described as burning pain, occurring in the absence of relevant visible findings or a specific, clinically identifiable, neurologic disorder.” Therefore, the term vulvodynia was reserved for those cases in which the pain could not be attributed to an identifiable “visible” cause. Since 2003, the category of identifiable causes of vulvar pain has evolved substantially, as have the potential factors associated with vulvodynia. These developments are based on the results of numerous studies examining a wide range of possible etiologic factors (eg, inflammatory, genetic, musculoskeletal, neurosensory, neuropathic) and treatment avenues (eg, oral medication, pelvic floor physical therapy, surgical intervention, psychologic intervention). These studies have also led to the conclusion that vulvodynia is likely not one disease but a constellation of symptoms of several (sometimes overlapping) disease processes that benefits most from a range of treatments based on individual presentation. These studies have widened the scope of etiologic considerations and have resulted in the need to update the description and nomenclature of persistent vulvar pain. In addition, several important pain characteristics of vulvodynia have been introduced (eg, primary and secondary status; intermittent and constant pain pattern). Bornstein 2016 Differential Diagnosis

49 VULVODYNIA ASSESSMENT COMPONENTS OF THE EXAMINATIONAfter all infectious, inflammatory, neoplastic, neurologic, and other disorders are identified and treated, women are assessed for vulvodynia through a five-step examination, as described in the following slides. Step 1: Visual Examination Step 2: Cotton-Swab Examination of the Vulva and Vulvar Vestibule Step 3: Neurosensory Examination Step 4: Pelvic Floor Muscle Examination Step 5: Evaluation of Pain Comorbidity & Contributing Factors Differential Diagnosis

50 VULVODYNIA ASSESSMENT SUBJECTIVE FINDINGS: “WHERE DOES IT HURT?”Generalized Vulvodynia “It hurts all over, all of the time.” Provoked Vestibulodynia “It hurts at the opening only with touch or pressure.” As shown on the left, most women with generalized vulvodynia report spontaneous pain in multiple areas of the vulva. Pain tends to be constant, but may be intermittent in some women. Although symptoms are spontaneous, they tend to worsen with provocation. Periods of unexplained pain relief and/or flares can occur. Erythema may or may not be present. This subtype affects 20% of those reporting chronic vulvar pain symptoms (Harlow 2003). As shown on the right, women with PVD report provoked pain only within the vulvar vestibule. Erythema may co-occur. This subtype affects 80% of those with vulvar pain (Harlow 2003). A subset of women report spontaneous widespread vulvar pain, as well as provoked pain localized to the vestibule. The above subtypes may coexist in some women (Reed 2003, Edwards 2004). Less prevalent (20%) subtype More prevalent (80%) subtype Differential Diagnosis 50

52 VULVODYNIA ASSESSMENT STEP 2: COTTON SWAB EXAMINATION OF THE VULVAUsing a cotton swab, test for allodynia, hypo- and hyperalgesia by applying gentle pressure to the following areas: 1-2 inner thigh 3-5 labia majora 6-8 interlabial sulcus 9 clitoris, clitoral hood 10 perineum 11 sites within vestibule (next slide) 1 9 Current guidelines recommend that a cotton swab test be performed (Haefner 2005). The 11 sites shown on this diagram should be tested for allodynia and hypo- or hyperalgesia by applying gentle pressure with a dry cotton swab (just enough to slightly indent the skin). If symptoms are provoked and localized to the vestibule, a more thorough evaluation of the vestibule is warranted and is described in the next slide. 3 6 4 7 11 5 8 For each site, the patient: Rates the pain severity (VAS score) Describes the pain character (burning, raw, etc.) 10 2 Differential Diagnosis

54 VULVODYNIA ASSESSMENT STEP 3: NEUROSENSORY EXAMINATIONInstruct the patient on ‘cotton’ vs. ‘pin- prick’ sensation by touching her outer thigh (just above the knee) with the cotton portion, followed by the wooden portion, of the cotton swab Using the cotton swab, gently stroke (upwards) each of the sensory dermatomes Note sensation (normal, allodynia, hypo- sensitive), pain score, pain character (eg, sharp, burning, shooting), and right- to left- side differences Break the cotton swab in half and repeat exam with the sharp wooden portion of the swab using punctate pressure (apply light pressure for 1 sec) in each dermatome • Note sensation (normal, allodynia, hypo- sensitive), pain score, pain character (eg, sharp, burning, shooting), and right- to left-side differences NIH-funded foundational work at the University of North Carolina at Chapel Hill is currently ongoing to refine a vulvovaginal neurosensory examination (described in this slide). Current prospective patient-reported outcomes studies are underway to delineate the exam components that are clinically relevant and predictive of treatment response (PI Zolnoun, NIH Grant 5K23HD053631, description available at: https://projectreporter.nih.gov/project_info_results.cfm?aid= &icde=0). From ongoing NIH Grant 5K23HD053631 Differential Diagnosis

56 VULVODYNIA ASSESSMENTSTEP 5: EVALUATION OF PAIN COMORBIDITY & CONTRIBUTING FACTORS As a consequence of living with a poorly understood, under-recognized genital pain disorder, women commonly report emotional distress and sexual impairment. Comorbid pain syndromes are also common, including: Interstitial Cystitis | Irritable Bowel Syndrome | Endometriosis Orofacial Pain (TMJ) | Chronic Headache (Migraine, Tension Type) Fibromyalgia | Chronic Fatigue Syndrome Assessment of comorbid disorders is important in selecting therapies that target all factors contributing to a woman’s current pain state, including: Pain (location(s), intensity & interference) Emotional Functioning Sleep Interference (both falling asleep & staying asleep) Physical Functioning Sexual Functioning Women with vulvodynia commonly report suffering from comorbid pain disorders, mood/sleep alteration, and sexual impairment. It is vital to assess all of the factors that are contributing to a woman’s current pain state to delineate the most appropriate components of an individualized, multidisciplinary treatment regimen. In a 2008 literature review, Desrochers critically examined studies on the psychosexual aspects of vulvodynia and concluded that, despite the presence of methodologic limitations, some findings were consistently replicated. Overall, women with vulvodynia demonstrated impaired sexual functioning, including lower levels of sexual desire, arousal, and frequency of intercourse. Additionally, questionnaires revealed that anxiety, fear of pain, hypervigilance and depression were more prevalent among these women. Desrochers concluded that more rigorous studies are needed to establish whether psychosexual variables exacerbate and/or maintain vulvodynia. A growing body of literature documents the association between vulvodynia and other chronic pain conditions. Warren (2008) proposed that vulvodynia may be a referred pain of interstitial cystitis (IC) in many cases. Several authors have proposed that both IC and vulvodynia are syndromes of the urogenital sinus-derived epithelium (McCormack 1990, Burrows 2008). Peters (2008) speculated that the conditions may be linked by common pelvic floor muscle dysfunction. Others have proposed that a common pathway may stimulate a single disease process (Kennedy 2007), or that in some women, IC and vulvodynia may be the same disease (Peters 2008). Recently, researchers have explored the relationship between vulvodynia and orofacial pain, specifically temporomandibular disorders. Zolnoun (2008) speculated that a subset of vulvodynia patients may suffer from a widespread musculoskeletal pain disorder influenced more by genetic makeup and central nervous system dysfunction than by an inflammatory process in the vulva. Kennedy (2007) proposed that: irritable bowel syndrome (IBS) may predispose women to certain vulvar conditions (perhaps by the irritant nature of diarrhea, for example), treatment for vulvar conditions may lead to bowel symptoms, or both conditions may represent a “pelvic floor pain disorder.” When studying the relationship between fibromyalgia and vulvodynia, Pukall (2005, 2006) proposed that the mechanisms involved in vulvodynia may be genital-specific in some women and possibly centrally mediated in others. Whether the generalized sensitivity or vulvar pain occurs first is unknown. For example, an untreated vulvar irritation could lead to central changes in sensory processing in genetically predisposed women, resulting in altered central pain processing and a widespread increase in sensitivity. On the other hand, women with vulvodynia may be more sensitive to pain in general and develop vulvar pain through a locally occurring event, such as a vulvar injury. See Comorbidity References. Differential Diagnosis

57 VESTIBULODYNIA: A DIAGNOSTIC ALGORITHM NEUROPROLIFERATIONVESTIBULODYNIA WITH TENDERNESS THROUGHOUT ENTIRE VESTIBULE NEUROPROLIFERATION ACQUIRED NEUROPROLIFERATIVE VESTIBULODYNIA CONGENITAL NEUROPROLIFERATIVE VESTIBULODYNIA This proposed diagnostic algorithm for vestibulodynia has been adapted from King M, Rubin R, Goldstein A. Current Uses of Surgery for the Treatment of Genital Pain. Current Sexual Health Reports. 2014;6: Shown on this slide are 2 potential causes of pain that affect the entire vestibule. King et al. postulate that if the entire vestibular endoderm (mucosa) is painful, it is likely that there is a pathologic process occurring in this tissue. The next 3 slides show additional causes of vestibulodynia with different underlying pathologic mechanisms. Subtle differences in the history (HX) and physical examination (PE) may help to differentiate between potential causes of vestibulodynia, which may lead to disease-specific treatments. HX: Allergic reaction, chronic yeast infection, polymorphisms in IL1RA, MBL, IL1B, associated with urticaria, hives, sensitive skin HX: Pain since first tampon use, speculum insertion, and coitarche. No pain free sex. Late coitarche > 25 years old. PE: Tenderness of the entire vestibule from Hart’s line to the hymen, often with erythema that worsens after touch with cotton swab. Umbilical hypersensitivity in approximately 60% of these women. PE: Tenderness of the entire vestibule from Hart’s line to the hymen, often with erythema that worsens after touch with cotton swab. Umbilical hypersensitivity in approximately 60% of these women. LABS: increased density of c-afferent nociceptors if using S-100 of PGP 9.5 LABS: increased density of c-afferent nociceptors if using S-100 of PGP 9.5 Differential Diagnosis

58 VESTIBULODYNIA: A DIAGNOSTIC ALGORITHM INFLAMMATORY VESTIBULODYNIAVESTIBULODYNIA WITH TENDERNESS THROUGHOUT ENTIRE VESTIBULE INFLAMMATORY VESTIBULODYNIA HX: Chronic infections, allergic reactions, copious yellowish discharge. PE: Erythema (redness), leukorrhea (thick discharge), induration (hardening of soft tissue), vaginal mucosal tenderness, cervicitis/ ectropion (inflammation of the outer cervix) CAUSES: Desquamative inflammatory vaginitis, chronic candidiasis, latex allergy/semen allergy This proposed diagnostic algorithm for vestibulodynia has been adapted from King M, Rubin R, Goldstein A. Current Uses of Surgery for the Treatment of Genital Pain. Current Sexual Health Reports. 2014;6: DESQUAMATIVE INFLAMMATORY VAGINITIS RECURRENT CANDIDIASIS HX: Copious yellow vaginal discharge that ruins underwear or requires a panty liner, vulvar pruritus where discharge dries PE: Copious leukorrhea, vaginal mucosa erythema, cervicitis, cervical ectropion CAUSES: Unknown, but current hypothesis is either infection of unknown pathogen, erosive lichen planus, vulvovaginal atrophy, or cervical ectropion. PE: Erythema, induration, thin fissures, peri-anal erythema. Discharge is often thin and yellow, not thick and white (cottage cheese-like). LABS: Hyphae and increased WBCs on wet mount. Positive cultures CAUSES: Diet high in simple sugars, antibiotics, OCPs Differential Diagnosis

59 VESTIBULODYNIA: A DIAGNOSTIC ALGORITHM HORMONALLY ASSOCIATED VESTIBULODYNIAVESTIBULODYNIA WITH TENDERNESS THROUGHOUT ENTIRE VESTIBULE HORMONALLY ASSOCIATED VESTIBULODYNIA PE: Gland ostia are erythematous, mucosal pallor with overlying erythema, decreased size of labia minora and clitoris LABS: High SHBG, low free testosterone, low estradiol CAUSES: Hormonal contraceptives, spironolactone, Tamoxifen, aromatase inhibitors, oophorectomy, amenorrhea, lactation This proposed diagnostic algorithm for vestibulodynia has been adapted from King M, Rubin R, Goldstein A. Current Uses of Surgery for the Treatment of Genital Pain. Current Sexual Health Reports. 2014;6: Differential Diagnosis

60 OVERACTIVE PELVIC FLOOR MUSCLE DYSFUNCTIONVESTIBULODYNIA: A DIAGNOSTIC ALGORITHM PELVIC FLOOR MUSCLE DYSFUNCTION AND PUDENDAL NEURALGIA VESTIBULODYNIA TENDERNESS ONLY IN THE POSTERIOR VESTIBULE TENDERNESS EXTENDS OUTSIDE OF THE VESTIBULE OVERACTIVE PELVIC FLOOR MUSCLE DYSFUNCTION This proposed diagnostic algorithm for vestibulodynia has been adapted from King M, Rubin R, Goldstein A. Current Uses of Surgery for the Treatment of Genital Pain. Current Sexual Health Reports. 2014;6: In this slide are the potential causes of pain in the posterior vestibule or pain that extends beyond the vestibule. King, et al postulate that if only part of the vestibular endoderm is painful, it is not likely that there is an intrinsic pathologic process occurring within the vestibular tissue. More likely, pain affecting only part of the vestibule is the result of a pathologic process extrinsic to the vestibule such as overactive pelvic floor muscle dysfunction (also known as vaginismus or levator ani syndrome). Tenderness that extends outside of the vestibule is likely pudendal neuralgia. PUDENDAL NEURALGIA HX: Urinary symptoms (frequency, sensation of incomplete emptying, hesitancy) if it involves coccygeus muscle. Constipation, rectal fissures, hemorrhoids if it involves puborectalis. Associated with anxiety, low back pain, scoliosis, hip pain, “holding urine,” excessive core strengthening exercises. HX: Often unilateral pain or significantly worse on one side. Pain can extend to the clitoris, labia, perineum, or anus and the inner thigh. History of coccyx trauma, history of hip pain or labral tear. Pain is usually better with lying prone or standing, worse with sitting. Pain improves temporarily with pudendal nerve block. PE: Pain at 4, 8 o’clock if hypertonus of pubococcygeus muscle. Pain at 6 o’clock if hypertonus of puborectalis muscle. PE: The pudendal nerve is tender when palpated at ischial spine on vaginal exam. The obturator internus muscle is usually very tender, unilateral or significantly greater on one side. Differential Diagnosis 60

61 Individualized Multidisciplinary Treatment

62 GENERAL PRINCIPLES Scientific level of evidence for almost all treatments is poor with very few RCTs. Individualized, Multidisciplinary Treatment Regimen Recommended Components of an individualized, multidisciplinary, biopsychosocial treatment approach are selected after identifying vulvodynia subtype and contributing factors (Jodoin 2011, Spoelstra 2011, Stockdale 2014). Multidisciplinary treatment results in reduced pain level, improvement in sexual functioning as well as increased patient knowledge, gain of tools/skills, improved mood and psychological well-being, gain of validation and support, and empowerment (Sadownik , Brotto 2015). See Andrews 2011 for an evidence-based review. Individualized Multidisciplinary Treatment

63 GENERAL PRINCIPLES Treatment Outcome Varies, but Majority Improve with Treatment As such, it can take many months to identify a treatment regimen that is helpful, but the majority of women will improve with treatment for variable periods of time (Ventolini 2009). Treatment response varies among patients, likely due to heterogeneity of underlying etiology. There is currently little knowledge to predict treatment outcome, although studies are ongoing. - Remission rates differ among women, underscoring the heterogeneity of vulvodynia, and remission may occur without treatment (Davis 2013, Nguyen ). - Heddini (2012) found that successful treatment was more likely in women with fewer concomitant pain disorders, and lower response rates were found in women with primary, rather than secondary, PVD. See Andrews 2011 for an evidence-based review. Individualized Multidisciplinary Treatment

64 COMPONENTS OF THE PROVIDER/PATIENT RELATIONSHIPBelieve the patient Clearly define realistic objectives and adapt management style Avoid making her feel responsible for failure Ask “how” the pain persists rather than “why” Avoid overestimating secondary benefits Avoid making her passive and dependent Labat 2010 Individualized Multidisciplinary Treatment

65 INDIVIDUALIZED MULTIDISCIPLINARY TREATMENTFirst step is vulvar* self-care, eg, avoid all vulvar irritants, and chronic pain self-care Oral “Pain-Blocking” Medications (1) ^ Tricyclic antidepressants (amitriptyline, nortriptyline) (1, 2-4, 28, 32, 33, 91) ** * Patient recommendations for vulvar self-care can be viewed at: ^ Detailed dosing and side effect information/charts for oral (and topical) medications used to treat vulvodynia are contained in The Vulvodynia Guideline, which can be viewed/downloaded at: ** In the medical literature, only 2 randomized controlled trials (RCTs) have evaluated the efficacy of oral tricyclic antidepressants. Neither randomized controlled trial found positive results (ie, the treatment provided only minimal relief of vulvar pain). These studies, however, included women with localized and generalized vulvodynia, as well as women with provoked and unprovoked vulvodynia, so treatment efficacy for specific subgroups is unknown. Despite their widespread use, even fewer efficacy data are available on anticonvulsants than on tricyclic antidepressants, with only 3 retrospective case series conducted to date. Even though these studies reported positive findings, there were no control groups. The first RCT evaluating gabapentin for treatment of vulvodynia is ongoing (Brown CS, Foster DC, Bachmann GA. A Controlled Trial of Gabapentin in Vulvodynia: Biological Correlates of Response). See the following website for more information, https://clinicaltrials.gov/show/NCT Anticonvulsants (gabapentin, pregabalin, lamotrigine, topiramate oxcarbamazepine) (1, 5-9, 105, 106) SSNRIs (duloxetine, venlafaxine, milnacipran) (1, 132) In severe cases, or to manage symptoms while the dose of a long-term medication is titrated upward, other pain-relieving medications (eg, short-term opioids) can be used See Treatment References Individualized Multidisciplinary Treatment

66 INDIVIDUALIZED MULTIDISCIPLINARY TREATMENTTopical Formulations Compounded topical formulations can be used in conjunction with medications (or other treatments) Topicals contain either a single active ingredient or a combination of ingredients (anesthetic, antidepressant, anticonvulsant) (1, 10, 30-35, 92, 109, 110, 131) -Topical use of benzocaine and diphenhydramine should be avoided due to potential sensitization and irritation (108) -Topicals not found useful* Discontinuation of oral contraceptives (OC) and use of a topically formulated estrogen (and sometimes testosterone) cream is recommended for cases in which OC use is suspected to play a role in symptom development and/or maintenance (1, 97, 103, 104) * Nifedipine was not better than placebo among women with vulvodynia in a double-blind study (107). Other topicals that are not useful include corticosteroids, progesterone, and antifungals (108). See Treatment References Individualized Multidisciplinary Treatment

67 INDIVIDUALIZED MULTIDISCIPLINARY TREATMENTLimited studies of multilevel nerve blocks (subcutaneous, pudendal, caudal) demonstrate efficacy (48, 93, 111) Nerve Blocks Pudendal and/or caudal blocks of local anesthetic, or local anesthetic and steroid, have been used with varying degrees of success (11-15) See Treatment References. Individualized Multidisciplinary Treatment

68 INDIVIDUALIZED MULTIDISCIPLINARY TREATMENTPelvic Floor Muscle Therapy Pelvic floor muscle therapy, including various physical therapy techniques, biofeedback training, trigger point injections and use of vaginal dilators, has been found helpful in women who also exhibit pelvic floor muscle abnormalities, eg, spasm, weakness, instability (1, 20-23, 31, 34, 36-46, 94, 112). The efficacy of botulinum, Type A (BTA) has been evaluated in a double-blind placebo controlled RCT and 2 case series. Petersen et al. found no difference between administration of 100 u BTA versus placebo in level of pain, quality of life and sexual function in 64 women with provoked vestibulodynia (PVD) (82). In contrast, a prospective case series of 20 women with PVD, by Pelletier et al., found that 80% of women reported an improvement in pain and 72% were able to have sexual intercourse following a dose of 100 u of BTA. Quality of life and sexual function also improved (126). See Treatment References Individualized Multidisciplinary Treatment

69 INDIVIDUALIZED MULTIDISCIPLINARY TREATMENTPelvic Floor Muscle Therapy (cont.) Similarly, lower doses of Botox (35-50 u) were found to significantly reduce pain and oral medication use, and improve quality of life, in a retrospective study of 19 women with PVD. Botox is not recommended as a first-line treatment for PVD. It may be useful, however, in combination with pelvic floor physical therapy (127). For a comprehensive review, see References 47, 112. See Treatment References Individualized Multidisciplinary Treatment

70 INDIVIDUALIZED MULTIDISCIPLINARY TREATMENTPsychotherapy Adjunct cognitive-behavioral therapy, psychotherapy (individual or couples) and/or sex therapy focused on pain reduction, sexual rehabilitation and/or relationship enhancement may be helpful (26, 37, 42, 66, 95, 113) Eliminating stress may also be a contributing factor in symptom improvement (44) Neurostimulation Case reports of recalcitrant patients show benefit of spinal cord stimulation (16-18) See Treatment References Individualized Multidisciplinary Treatment 70

71 INDIVIDUALIZED MULTIDISCIPLINARY TREATMENTSurgery Vestibulectomy with Vaginal Advancement Involves the removal of a portion (or all) of the vestibule, with vaginal advancement Surgical technique/images (www.nva.org/shg3) Two procedures exclusively for women with provoked vestibulodynia: Modified Vestibulectomy Only the superficial painful tissue is removed and there is no vaginal advancement. Surgical technique/images (www.nva.org/vestibulectomy) Landry, et al provide a thorough review of surgical treatment studies (29). See Treatment References Individualized Multidisciplinary Treatment

72 INDIVIDUALIZED MULTIDISCIPLINARY TREATMENTSurgery (cont.) Most published results are based on Vestibulectomy with Vaginal Advancement. In this type of surgery, the vagina is pulled and sutured to the perineal skin, halfway between the vulvar introitus and the anus so that the sensitive mucosa-skin junction will not be in the introitus itself (128). Overall success rates for both procedures range from percent (29, 42, 49-60, 114, 115), but recurrences may occur in an unknown percentage of patients over a variable period of time (96). After surgery, physical and dilator therapy are often recommended and appear to help alleviate any remaining pelvic floor myalgia (53, 59). Careful patient selection is essential because it increases the likelihood of success with a surgical procedure. Researchers are studying factors that may predict surgical treatment success or failure (42, 52, 55, 59, 61-64, 96, 116). Landry, et al provide a thorough review of surgical treatment studies (29). See Treatment References Individualized Multidisciplinary Treatment

73 INDIVIDUALIZED MULTIDISCIPLINARY TREATMENTThese treatments, some of which are currently the focus of efficacy studies, are occasionally used to manage vulvodynia symptoms, depending on the case. Topical Steroids – Both improvement and worsening reported (32, 67). Recently, a review article concluded that steroids are not effective (127). Subcutaneous Steroid/Anesthetic Injections – Some improvement noted (71-73). Case report noted improvement following remote foci anesthetic injection (117). Neogyn (cutaneous lysate skin cream containing human cytokines) – Initial study demonstrated decreased inflammation and intercourse-related pain (102). Vaginal Diazepam – Initial case studies showed decreased levator muscle pain and vulvar pain. However, it is uncertain whether the effect is local or systemic (98, 118, 119). See Treatment References Individualized Multidisciplinary Treatment

74 INDIVIDUALIZED MULTIDISCIPLINARY TREATMENTTreatments lacking proof of efficacy: Diet Modification - Although a minority of women claim benefit from a low oxalate/calcium citrate regimen, studies have found no difference in the amount of urinary oxalate excreted by women with vulvodynia and controls (1, 24, 32, 74, 75). A case-control, population-based study found no association between increased consumption of foods with high oxalate content and risk of vulvodynia (25). Some women report that eliminating acidic and/or high sugar foods provides some symptom-relief. Interferon Injections - Although initial data was promising, recent clinical data indicate a much lower or non-existent efficacy rate (1, 32, 68, 69). Topical Cromolyn - The initial study found little efficacy in women who had recalcitrant symptoms (70). See Treatment References Individualized Multidisciplinary Treatment

75 INDIVIDUALIZED MULTIDISCIPLINARY TREATMENTExperimental treatments that have been the focus of several recent journal publications, but are not widely used at this time, include: Leukotriene Receptor Antagonist: One controlled study of women with PVD showed a 50% improvement in symptoms (83) Topical Capsaicin: Initial report of improvement in pain and dyspareunia (85) Enoxaparin Injections: Decreased vestibular sensitivity and dyspareunia (101) Topical Nitroglycerin: Initial report of improvement in pain and dyspareunia, but headache was a limiting side effect (84) KTP-nd: YAG Laser Therapy: Initial report showed reduced dyspareunia and improved sexual satisfaction (86) See Treatment References Individualized Multidisciplinary Treatment

76 INDIVIDUALIZED MULTIDISCIPLINARY TREATMENTPhotodynamic Therapy - Initial report of reduction in overall symptoms, but no improvement in intercourse-related pain (87) Transcutaneous Electrical Nerve Stimulation – Reports of improvement in vulvar pain, intercourse-related pain and sexual functioning (88, 89, 99, 120, 121) See Treatment References Individualized Multidisciplinary Treatment

77 INDIVIDUALIZED MULTIDISCIPLINARY TREATMENTAdditional experimental treatments that have been the focus of several recent journal publications, but are not widely used at this time, include: Palmitoylethandamide - Inconsistent effectiveness when used in combination with TENS and other agents (99, 122, 123) Transcranial Direct Current Stimulation - One case report of a refractory patient who responded well (19) Alternative therapies: Hypnotherapy - Limited findings for hypnotherapy noted significant decrease in pain associated with intercourse and increase in sexual satisfaction in 9 women with vestibulodynia (129, 130). Acupuncture - Limited reports of improvement in vulvar pain and dyspareunia, including 1 randomized study comparing patients with vulvodynia to waitlist controls (133, 134). Sacral Neuromodulation - One case report described sustained pain improvement at 2 years follow-up (90) Motor Cortex Stimulation – Two cases showed decreased pain, increased daily activities and quality of life after failure of conventional neuromodulation, eg, spinal cord stimulation (100). Peripheral Neuromodulation - Case report described pain improvement (with 1 year follow-up) (124) Alternative Therapies Pulsed Radiofrequency - Case report of successful use for chronic vulvodynia (125) See Treatment References Individualized Multidisciplinary Treatment

78 USING VALIDATED EVIDENCE-BASED TOOLS TO TRACK KEY DOMAINS & TREATMENT OUTCOME• Key domains important to assess and track over time include: • NIH PROMIS^ also has numerous tools using computerized adaptive testing to measure outcomes. - Pain (location(s), intensity & interference) - Physical, emotional and sexual functioning - Sleep interference (both falling asleep & staying asleep) - Treatment side effects • Several web-based and smartphone apps are currently available online for use by pain sufferers, including those listed below, however, most do not provide information to patients’ clinicians.^^ PainTracker is an evidence-based tool available to individual health care providers for use to track key domains and treatment outcomes over time. A quick overview of the program, interface, and questionnaire can be viewed at: Request login information to review the web interface from: https://paintracker.cirg.washington.edu/demo/users/login. * The Female Sexual Function Index (FSFI) can be viewed/downloaded here: ^ Instruments available through NIH PROMIS can be viewed here: https://www.assessmentcenter.net/documents/InstrumentLibrary.pdf. ^^A recent study found that smartphone tracking systems promoted excellent compliance with weekly tracking (135). Examples include: WebMD Pain Coach, My Pain Diary, Chronic Pain Tracker, and Manage My Pain. • Female Sexual Function Index* can be used to monitor sexual function and satisfaction. Individualized Multidisciplinary Treatment

79 Key Summary Points Vulvodynia, defined as chronic vulvar pain of at least 3 months duration that occurs in the absence of a clear identifiable cause, is a widely prevalent, misdiagnosed, and under-researched pain disorder affecting women of all ages and ethnicities. It negatively affects women’s physical, emotional and sexual health. The vulva contains tissues derived from both the endoderm and ectoderm. It is innervated by the ilioinguinal, genitofemoral and pudendal nerves. Further, its proper functioning relies on both superficial and deep pelvic floor musculature.

80 Key Summary Points Women/adolescents who are likely to have a clinical diagnosis of vulvodynia report: i) genital pain, ii) genital burning for more than 3 months, iii) 10 or more episodes of pain on contact with tampon insertion, intercourse or gynecologic exam, and iv) pain on contact that limits/prevents intercourse. Although vulvodynia’s pathophysiology remains inconclusive, research supports the theory that multiple mechanisms predispose, trigger and perpetuate symptoms. Heterogeneous mechanism-based subgroups demonstrate variable degrees of peripheral and central nervous system sensitization, vestibular tissue changes and pelvic floor muscle dysfunction.

81 Key Summary Points The vulvodynia subtype is first classified by location: generalized (several areas of the vulva) vs. localized (a specific vulvar region) and then by provocation (provoked, spontaneous or mixed). The two most common subtypes of vulvodynia are generalized vulvodynia (spontaneous pain in several vulvar areas) and provoked vestibulodynia (provoked pain localized to the vulvar vestibule). After all known infectious, inflammatory, neurologic, neoplastic and other causes of vulvar pain are ruled out, a thorough vulvodynia assessment includes: i) visual exam of the vulva, ii) cotton swab exam of the vulva and vulvar vestibule, iii) neurosensory exam, iv) pelvic floor muscle evaluation, and v) an evaluation of pain comorbidity and contributing factors.

82 Key Summary Points Components of an individualized, multidisciplinary, biopsychosocial treatment regimen are selected after identifying the vulvodynia subtype and contributing factors. Due to vulvodynia’s heterogeneity, treatment response varies among women. As a result, it can take time to identify a helpful regimen, but the majority of women do improve with treatment. It is vital to assess and track key pain-related domains over time as women undergo treatment. Several validated easy-to-use tools are currently available to track pain intensity and interference; physical, sexual and emotional function; sleep interference; and treatment side effects.

83 SELECTED REFERENCES Selected Journal References available at 2015 Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia (Bornstein) Medical and Physical Predictors of Localized Provoked Vulvodynia (Bohm-Starke) Vulvodynia: Diagnosis and Management (Reed) Vulvodynia: An Evidence-Based Approach to Medical Management (Andrews) Vulvodynia-An Evidence-Based Literature Review and Proposed Treatment Algorithm (De Andres) The Vulvodynia Guideline (Haefner) 2013 Vulvodynia Guideline Update (Stockdale) Vulvodynia Interventions – Systematic Review and Evidence Grading (Andrews)

84 SELECTED REFERENCES Proceedings of the 2003 & 2011 NIH Conferences available at Selected Reference Textbooks available at Female Sexual Pain Disorders: Evaluation and Management (Goldstein, Pukall, Goldstein) The Vulva: Anatomy, Physiology and Pathology (Farage, Maibach)

85 PATIENT RESOURCES Patient Booklets available at www.nva.org/shgSelf-Help Guide: features important self-help strategies for alleviating vulvar pain and maintaining sexual intimacy Conception to Pregnancy Guide: includes information on conception through the postpartum period Partner Guide: helps partners to have a better understanding of vulvodynia and the challenge of living with someone who has it Disability Guide: provides step-by-step guidance that will help vulvodynia sufferers compile and submit a successful disability claim NVA Brochure available at Self-help tips available at Reference Books available at