- Email: [email protected]
Vulvodynia
Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
Contents lists available at ScienceDirect
Best Practice & Research Clinical Obstetrics and Gynaecology journal homepage: www.elsevier.com/locate/bpobgyn
6
Vulvodynia Erin Eppsteiner, MD, Fellow Associate a, *, Lori Boardman, MD, ScM, Professor of Obstetrics and Gynecology b, 1, Colleen K. Stockdale, MD, MS, Clinical Associate Professor a, 2 a
Department of Obstetrics and Gynecology, 200 Hawkins Drive, University of Iowa, Iowa City, IA, USA University of Central Florida College of Medicine, 12201 Research Parkway, 3rd Floor, Orlando, FL 32816-0116, USA
b
Keywords: vulvodynia vestibulodynia vulvar pain dyspareunia
Vulvodynia is a complex disorder reported by up to 16% of women in the general population. While most patients describe it as burning, stinging, irritation, or rawness, it is underreported and underrecognized by providers. Vulvodynia is costly both economically and psychologically due to its negative impact on quality of life. Vulvodynia is a diagnosis of exclusion with unknown etiology and may involve multiple sources of pain in the same woman. Thus, there are no clinical or histopathologic criteria for the diagnosis other than consideration and careful evaluation to exclude other causes of pain. Successful therapy often requires a multidisciplinary approach with more than one therapeutic intervention to address the physical, psychological, psychosexual, and relationship components. © 2014 Elsevier Ltd. All rights reserved.
Introduction The International Society for the Study of Vulvovaginal Disease (ISSVD) most recently defined vulvodynia as “vulvar pain occurring in the absence of an underlying recognizable disease.” [1]. Vulvodynia is further classified based on the site of the pain, whether it is provoked, unprovoked, or mixed and subcategorized as generalized or localized.
* Corresponding author. Tel.: þ1 319 384 8685; Fax: þ1 319 384 8620. E-mail address: [email protected] (E. Eppsteiner). 1 Tel.: þ1 407 823 0500; Fax: þ1 407 823 1856. 2 Tel.: þ1 319 384 6849; Fax: þ1 319 384 8620.
http://dx.doi.org/10.1016/j.bpobgyn.2014.07.009 1521-6934/© 2014 Elsevier Ltd. All rights reserved.
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
1001
Vulvodynia significantly impacts patients' quality of life and can be the source of physical, psychosexual, and relationship distress for affected women. Similarly, clinicians experience frustration in diagnosing and treating vulvodynia in an efficient and effective manner. The cost of vulvodynia management in the United States is estimated to be $31 to $72 billion per year [2]. Unfortunately, there remains a relative paucity of research despite the impact on women and society. Epidemiology Among women living in the United States, the prevalence of vulvodynia has been estimated to range from 4% to 16% [3e6]. A clinic-based prevalence study identified 15% (of 210 women) with localized vulvodynia [4]. Half of the patients reported lifelong symptoms whereas a significant proportion of the remaining patients reported onset following childbirth [4]. Subsequently, a populationbased study found nearly 16% (of 4915 women) reported a 3-month history of vulvar pain [3]. Localized vulvodynia was confirmed in 78% who presented for clinical exam [3]. Symptoms were associated with younger age, earlier menarche, and pain with first tampon use [7]. White and African American women had similar prevalences, whereas Hispanic women were 80% more likely than either white or African American women to experience vulvar pain [3]. While 60% of women reporting vulvar pain sought treatment (the majority by at least three providers), the diagnosis remained elusive [3,7]. Similarly, a population-based study including >2200 women found that about half of women meeting vulvodynia criteria sought treatment for their symptoms and only 1.4% were diagnosed with vulvodynia [5]. Because vulvodynia is a diagnosis of exclusion, findings from epidemiologic studies without clinical confirmation should be interpreted with caution. Etiology While many theories regarding associated factors and vulvodynia have been suggested, evidence for the underlying etiology remains elusive. Embryology Vulvodynia has been associated with other chronic pain conditions including painful bladder, irritable bowel syndrome, and fibromyalgia [8,9]. Given the shared embryologic origin (urogenital sinus) for the lower genital tract, a unifying mechanism of pain development has been proposed. Neuropathic pain Perhaps the most compelling origin of vulvodynia is a neuropathic pain disorder. Neuropathic pain is defined by the International Association for the Study of Pain as a complex pain initiated by a primary lesion or dysfunction of the nervous system [10]. The pain described by patients with vulvodynia is similar in nature to that described by patients with neuropathic pain such as postherpetic neuralgia and diabetic neuropathy. Patients most often describe a burning pain which can be constant, but may be exacerbated by certain triggers. Studies suggest both central and peripheral responses to neuromodulating agents, further supporting this etiology. Additionally, patients with vulvodynia have an increase in number and caliber of nerves, specifically pain-sensing nociceptors, which may lend to increased sensitivity [11e13]. Infection Potential infectious etiologies have been investigated [14e16]. While Farage et al. reported that up to 80% of women with vulvodynia have a self-reported history of recurrent vulvovaginal candidiasis, Bornstein noted that treatment with fluconazole did not improve vulvar pain symptoms among 40 women with vulvodynia, several of whom had culture-proven vulvovaginal candidiasis [17,18].
1002
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
However, it is unclear whether symptoms were related to the topical therapies used for treatment or the candidal infection. The human papillomavirus (HPV) was also implicated as a factor in the development of vulvodynia [19]. However, subsequent studies have not demonstrated an association between HPV and vulvodynia [20e23]. Thus, HPV noted among women with vulvodynia is likely a reflection of the general prevalence rather than a true association. Inflammation Based on the presence of vulvar erythema, older terminology referred to vestibulitis, “-itis” signifying inflammation. This was initially corroborated by tissue samples of patients with vestibulodynia who were noted to have an inflammatory infiltrate. However, subsequent studies noted the presence of an inflammatory infiltrate in asymptomatic controls [24,25]. Thus, the presence of inflammation, either clinically or histologically, is not a diagnostic marker for vulvodynia. Genetics Genetic features may predispose women to the development of neuropathic pain. Specifically, allele 2 of interleukin 1 beta (IL-1 beta) receptor antagonist (an inflammatory mediator) may be associated with an exaggerated response to inflammation due to decreased ability to downregulate the inflammatory activity [14,26e28]. Hormonal influence Based largely on anecdotal evidence, vulvodynia was noted to occur in women with possible alterations in hormonal milieu, specifically resulting from hormonal birth control. While several studies have demonstrated an association with combined hormonal contraception and the risk of developing vulvodynia, other studies have not [29e34]. Dietary influences The association of dietary oxalates and vulvodynia was based on a single case report describing the complete relief of vulvodynia in a woman following a low-oxalate diet with calcium citrate supplementation [35]. Two subsequent case-controlled studies found no difference in oxalate excretion nor an association with vulvodynia [36,37]. Thus, dietary oxalate consumption is not currently recommended for the management of vulvodynia. Anatomic Pelvic floor dysfunction can be a predisposing or coexisting condition. While it remains unclear whether pelvic floor dysfunction is a result of chronic pain from vulvodynia or a precipitating factor, physical therapy and biofeedback can improve muscle tone and pain symptoms when present. Psychosocial Vulvodynia causes significant emotional and psychosocial distress in affected patients, and subsequently their families and their sexual partners. While it has been postulated that avoidance of intimacy may be due to an increased incidence of childhood physical or sexual abuse in women with vulvodynia, evidence remains contradictory [38e41]. Furthermore, women with vulvodynia were noted to share similar psychological characteristics to controls and have comparable marital satisfaction [42]. Regardless of which occurred first, pain or psychologic distress, targeted psychosocial therapy leads to improvement of pain for some patients [43].
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
1003
Prognosis A prospective study involving 239 women with provoked vestibulodynia noted significant improvement in pain ratings, sexual satisfaction, sexual function, and depressive symptoms (as assessed by Beck Depression Inventory) over 2 years, regardless of treatment modality [44]. While the most common treatments were physical therapy, sex/psychotherapy, and medical treatment, 41% received no treatment. The only single treatment with superior outcome was surgery; however, this treatment improved only depressive symptoms and did not affect pain [44]. Although this study is prognostically informational, it did not have the data to support the use of one treatment modality over another. Rather, this study supports the use of placebo-controlled trials to assess treatment outcomes beyond the apparent natural progression of provoked vestibulodynia. Diagnosis Women with vulvodynia present with varied complaints depending on the subtype of their disease. Most patients with vulvodynia complain of a burning or tearing pain which can be constant or intermittent, spontaneous (unprovoked) or provoked (i.e., with vaginal penetration during physical examination, sexual intercourse, or placement of a tampon.) Given that vulvodynia is a diagnosis of exclusion, careful history and physical examination to rule out other etiologies of pain is imperative. Patient history Patients presenting with vulvar pain should be queried regarding character and duration of symptoms; medical, psychosocial, and surgical history; sexual history; allergies; and previous treatments. One should specifically inquire about current products that patients are using (including both over-the-counter and prescribed topicals), as the vulvar skin is particularly sensitive to additives in commonly used hygiene products as well as to components of sanitary and laundry products. A menstrual history clarifies whether pain is associated with menses and whether the patient is in a hypoestrogenic state such as menopause. Contraception methods should be assessed as barrier protection can cause contact irritation, while some hormonal methods can contribute to atrophy. It should be noted whether the patient is sexually active, including number and gender of partners and whether lubricant, sex toys, or dilators are used. Risk of infection such as yeast should be assessed as symptoms can mimic those of vulvodynia. Regarding medical and psychosocial history, diagnoses such as irritable bowel syndrome, painful bladder syndrome, and depression have been associated with vulvodynia [9,45]. While history of physical or sexual abuse should be determined to assist with optimal patient management, childhood physical or sexual abuse should be queried as both have been found to be more prevalent in a population of women with vulvodynia [39]. Physical trauma or history of pelvic surgery (e.g., pelvic reconstruction, cystocele repair, rectocele repair, etc.) can contribute to the development of nerve injury and resultant pain. Thus, obstetric history including route of delivery, use of forceps/vacuum, birth weight, and resultant obstetrical trauma with mode of repair should be included. Finally, it should be noted whether the patient has been examined for these symptoms in the past and the outcomes from treatments rendered. Physical exam The physical examination should include an abdominopelvic exam with specific attention paid to vulvar findings. The vulvar exam should begin with visualization of the entire vulva. This includes inspection from the mons anteriorly to the perianal skin posteriorly and into the intertriginous zones lateral to the labia majora. Careful examination helps to assess for change in color, erythema, edema, mass, or lesion. Shaving and waxing, as well as piercings, should be noted as they can predispose the patient to folliculitis and further exacerbate symptoms. The absence of a normal hair pattern and normal vulvar architecture may otherwise be suggestive of vulvar dermatoses.
1004
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
Bilateral inguinal areas should be palpated to assess for lymphadenopathy. Further evaluation of the patient's pain requires palpation of the vulva. At this point, the patient should demonstrate by pointing to where the pain is most severe. Offering a mirror with the back of the examining table elevated can assist the patient and practitioner in locating her pain. The examiner should then use the cotton swab to assess for areas of point tenderness which would determine whether the pain is generalized or localized, provoked or unprovoked. Asking the patient if she has pain before palpation with the cotton swab can further elucidate if the pain is spontaneous (unprovoked). A single-finger palpation of the perineal muscles should be undertaken to assess for evidence of vaginismus. A bimanual examination may be performed if there is concern based on history that the symptoms may be caused by pain in the upper genital tract. Finally, as vulvar pain can be referred pain from other parts of the body, such as the back or hips, a musculoskeletal evaluation may be indicated. Further testing Additional testing should be based on the patient's history and clinical exam. We recommend a wet mount for microscopy, vaginal pH, and fungal culture. A biopsy is not necessary unless there is a focal lesion suspicious for neoplasia or there is concern for underlying pathology/dermatoses. Treatment Vulvodynia is often multifactorial in origin; thus, a multidisciplinary approach to treatment should be considered. The team of providers may involve sexual counselors, clinical psychologists, physical therapists, and pain specialists in addition to the primary treating provider. It is crucial to maintain communication among all involved treating providers to avoid duplication of therapy and optimize a cohesive treatment plan. It is critical to have a good working relationship with the patient. Any treatment approach should begin with a discussion including an explanation of the diagnosis and realistic treatment goals. A general guiding principle is to begin with those treatment options with the fewest side effects or potential complications. The patient should be counseled that follow-up is needed to evaluate treatment responses and adjust the therapeutic plan as needed to maximize pain reduction. The majority of therapeutic regimens for vulvodynia have been established based on expert opinion, clinical experience, and observational studies with no single best regimen identified. Few randomized controlled trials exist. Current modalities include vulvovaginal skin care guidelines; use of medical therapies including oral, topical, and injectable medications; biofeedback and physical therapy; psychosexual counseling; and surgical intervention, as well as complementary and alternative therapies. It is important to note that the majority of the research to date has focused on the treatment of vestibulodynia and less on the treatment of generalized vulvodynia. Additionally, modalities such as vestibulectomy do not apply to treatment of generalized vulvodynia. Skin care guidelines Products used on the vulva may incite contact irritation further contributing to vulvodynia. Thus, we recommend elimination of all potential irritants (Table 1). Additional recommendations include
Table 1 Common vulvar irritants. Perfumed laundry detergents Fabric softeners/dryer sheets Perfumed body soaps Feminine wipes Douches Pads and tampons with perfumes/avoid use of daily panty liner Topical medications
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
1005
cleansing the vulvar skin with warm water only and patting dry, use of white cotton underwear, and avoidance of tight-fitting clothing. The patient should be educated that lubrication is imperative for intercourse and encouraged to use plain unscented/unflavored silicone- or oil-based products that generally maintain their lubricating properties for longer than water-based products. The patient's household members and sexual partners should make similar changes regarding products in order to prevent cross contamination (from shared laundry) and continued irritation (from direct contact). A common barrier to implementing these changes is the patient report that they have “always used such methods and products” without prior difficulty. It is important to emphasize that product formulations as well as vulvar sensitivity can change over time. Thus, elimination of possible irritants is imperative for treating both localized and generalized vulvodynia. Clinicians should also consider elimination of prescription products and starting anew as patients can develop sensitivities to these products or the base in which they are prepared. Medical management Topical With all topical medications, it is helpful to use a mirror in the clinic setting and show the patient exactly how much and where to apply the medication to ensure they receive the desired effect and minimize local and systemic side effects. Some patients may develop worsening of discomfort with use of a topical medication, which may signify sensitivity to the medication and/or to the base in which it is prepared. As noted, ointments are better tolerated than creams due to additives, specifically drying agents, which tend to be present in cream preparations. If a patient develops sensitivity to multiple agents, evaluation may be warranted. Medication can then be compounded to avoid vehicles to which the patient is sensitive. Lidocaine The most commonly prescribed topical medication for the treatment of vestibulodynia is lidocaine (2e5%) in the form of a gel, cream, or ointment. It can be used as a palliative measure for sexual intercourse or it can be used to treat the skin. In the case of sexual intercourse, it should be applied 20e30 min prior to penetration or on an as-needed basis. Following application of 5% lidocaine ointment nightly for a mean of 7 weeks, 57% (of 61 patients) with vestibulodynia reported a significant (>50%) decrease in dyspareunia and 40% more women were able to have intercourse [46]. By contrast, a randomized, double-blinded, placebo-controlled trial compared the use of oral desipramine and topical 5% lidocaine cream as both monotherapy and combination therapy. The aim was to target both peripheral and central neuronal pathways, which would also potentially elucidate the origin of the neuropathic component of this diagnosis. All arms of the study, including the double placebo arm, demonstrated a decrease in vulvar pain. There was no significant difference between pain reduction in patients treated with placebo versus topical lidocaine monotherapy (33% vs. 20%) [47]. Yet another study compared the use of electromyographic biofeedback and topical lidocaine treatment over 4 months and found similar pain improvement in both groups [48]. The side effects of lidocaine include burning sensation at the site of application and toxicity which can be minimized by use of the smallest effective dose. Lidocaine 5% ointment (or 2% jelly) is most commonly prescribed for application 30 min before sexual activity [49]. Topical use of benzocaine and diphenhydramine should be avoided due to potential sensitization and irritation. Cromolyn Despite a case series demonstrating benefit, a randomized double-blind placebo-controlled study found cromolyn 4% cream to be no more effective than placebo in symptom reduction in women considered to have a possible allergic etiology of vestibulodynia [50]. Capsaicin Although observational studies demonstrated moderate improvement in dyspareunia in the majority of patients with vestibulodynia applying capsaicin >four times daily, treatment is often
1006
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
discontinued due to intolerance/discomfort with local application. This is not surprising given that capsaicin is the spicy element in hot chili peppers. Moreover, almost all patients who completed treatment required use of topical lidocaine or narcotic pain medication prior to the application of capsaicin and therefore it is unclear how much of the desired effect is attributed to capsaicin use [51,52]. Nifedipine While application of topical nifedipine has been shown to be successful in treating chronic anal fissure, a double-blind placebo-controlled trial demonstrated no difference in improvement in pain in women with vestibulodynia between the treatment and placebo groups (mean pain intensity improved in all arms of the study) [53]. Nitroglycerin Similar to nifedipine, nitroglycerine has demonstrated benefit for treating chronic anal fissure. A small prospective cohort study found 91% (of 34 women) with vulvodynia with introital dyspareunia noted improvement in overall pain following topical application of 0.2% nitroglycerine cream [54]. However, side effects including headaches, lightheadedness, dizziness, or fainting limit its use in clinical practice. Diazepam Due to its use in treatment of muscle spasm, observational studies primarily from the urology literature have evaluated the effect of vaginal diazepam on pain associated with pelvic floor dysfunction/hypertonicity [55,56]. While observational findings have suggested some improvement in a subgroup of women with vulvodynia, serum levels are similar to levels with systemic use, which raises concern for development of tolerance and substance dependence [56]. Gabapentin Based on success following oral gabapentin for neuropathic pain conditions and limited clinical observation with its use for vulvodynia (generalized and localized), the efficacy and tolerability of topical gabapentin were retrospectively evaluated. Twenty-eight (of 35 women with vulvodynia) demonstrated at least 50% improvement in pain scores. Furthermore, topical application was well tolerated [57]. Amitriptyline/baclofen Combined amitriptyline 2%, baclofen 2% cream was evaluated in a retrospective review of 38 women with vestibulodynia refractory to other medical treatment. Of this cohort, 71% identified a response of at least 30%, while 53% reported >60% improvement in dyspareunia [58]. Subsequently, the application of topical 2% amitriptyline twice daily was evaluated as a monotherapy in a prospective cohort of women with vestibulodynia over 3 months [59]. Fifty-six percent (of 150 patients) reported improvement, 10% of whom reported complete resolution of pain and pain-free intercourse [59]. Estrogen While an association between the use of combined hormonal contraceptives and vulvodynia remains controversial, a recent retrospective review of 50 premenopausal women using combined hormonal contraceptives with secondary vestibulodynia reported improvement in posttreatment pain scores following discontinuation of their medication and local application of topical estradiol and testosterone twice daily for an average treatment duration of 20 weeks [60]. Fibroblast lysate A recent crossover study evaluated the use of fibroblast lysate cream for treatment of vestibulodynia in 30 patients. There was a statistically significant (though clinically modest) decrease in erythema and dyspareunia with treatment over placebo [61]. Other topicals Topical steroids, progesterone, and antifungals have not been shown to be effective in the treatment of vulvodynia.
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
1007
Oral medications Antidepressants Antidepressant medications have been successfully used in the treatment of various chronic pain syndromes, not only for effects on depression which can accompany chronic pain, but also for effects on pain. Antidepressants have been shown to be effective in patients with and without depressive symptoms [62]. Additionally, patients report improvement in symptoms with low numbers needed to be treated [62]. As noted previously, a double-blind, placebo-controlled, four-arm study using oral desipramine and topical 5% lidocaine cream as both monotherapy and combination therapy was conducted. All arms of the study, including the double-placebo arm, demonstrated a decrease in vulvar pain. There was no significant difference between pain reduction in patients treated with placebo versus oral desipramine (33% vs. 24%) [47]. A cohort study noted at least 50% improvement among 87% participants following combined tricyclic antidepressant (TCA) combined with counseling and support for vulvodynia of which 47% of 32 patients reported complete relief [63]. However, the proportion of improvement attributed to the TCA is unclear given the use of combined therapy. Subsequently, in a prospective cohort evaluating the TCA effectiveness, 59% (of 83 women) using a TCA for vulvodynia improved by >50% in contrast to 38% (of 79 women) not using a TCA [64]. While antidepressant medications have not been directly compared, TCAs are the most studied and appear to be more effective than other classes. In reports of previously failed therapy with selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), TCAs were found to be successful in reducing vulvar pain [65]. There is evidence for the use of SNRIs in neuropathic pain, although this has not been studied in vulvodynia [66]. SSRIs are generally less effective than TCAs for pain, but the side-effect profile of SSRIs are generally better than the notorious anticholinergic side effects of TCAs. It is recommended that low doses be used initially and titrated based on patient tolerance and response. Common anticholinergic side effects with TCA use are dry mouth, blurred vision, constipation, drowsiness, and increased appetite. Many women will experience a modest weight gain with TCAs. Most side effects are short term and resolve once the patient is stabilized on therapy. It has also been reported that some antidepressants, typically the SSRIs and SNRIs, can have negative effects on sexual function [67]. This is not typically noted with the TCAs. Although this has not been well described in the vulvodynia literature, it warrants mention given that patients with vulvodynia are often struggling with poor sexual function and comorbid psychosexual conditions. Thus, disclosure is important and titrating adequate doses for pain control can be limited by patient tolerance of side effects. Antiepileptics In patients who cannot tolerate adequate doses of TCAs or report inadequate relief of vulvodynia, anticonvulsant medications are often considered. Antiepileptics are Food and Drug Administration (FDA) approved for treating other forms of neuropathic pain. Gabapentin has been the utilized and most studied anticonvulsant for all types of vulvodynia [49]. Other anticonvulsants useful for vulvodynia treatment in cohort studies include pregabalin, lamotrigine, and carbamazepine [68e71]. Similar to studies of other therapies for vulvodynia, randomized trials or comparative studies are not available. The side effects of gabapentin are similar to those noted with antidepressants (e.g., mild cognitive impairment, weight gain, and increased appetite), but are thought to be less severe. Generally, improvement in vulvodynia pain was noted following the use of topical and oral gabapentin as well as oral lamotrigine in observational studies [72]. However, whether the improvement in pain occurred because of therapy or represented a regression to the mean was questioned. No randomized trials studying the effectiveness of gabapentin against placebo have been performed. When prescribing antidepressant or anticonvulsant medications, it is important to attempt use for several weeks (e.g., 4e8 weeks) before determining the full effect. When discontinuing after stable use, it is important to taper the dose, as abrupt discontinuation can have significant effects similar to alcohol or benzodiazepine withdrawal including insomnia, restlessness, agitation, anxiety, and confusion.
1008
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
Injections Corticosteroid Thought to be due to anti-inflammatory effects, submucosal injection of corticosteroid has been reportedly successful at improving vulvar pain associated with vestibulodynia [51,73]. Botulinum toxin A Suggested following successful use in other pain syndromes, botulinum toxin may have a specific pain-modulating effect in addition to its paralytic effects [74]. While several small, open-label studies have shown improvement in symptoms with botulinum toxin at doses of 20e100 units, the only randomized, double-blinded, placebo-controlled trial demonstrated no improvement with 20 units over placebo in 64 women with vulvodynia [75]. Other injections A recent placebo-controlled study was undertaken to evaluate enoxaparin based on the increased presence of heparanase in the vestibule of women with vestibulodynia. While modest, 15 of 20 enoxaparin-treated women reported >20% reduction in pain compared to five of 18 women in the placebo group [76]. Vestibulectomy Surgical intervention is not generally considered first-line therapy due to the desire to pursue less invasive options. Thus, patients proceeding with surgical therapy have often failed a number of other medical therapies or interventions. Vestibulectomy is reserved for patients with vestibulodynia and not those with generalized unprovoked vulvodynia. A critical review of the literature to date suggests that vestibulectomy is successful in 60e90% of cases, whereas other nonsurgical therapies are 40e80% effective. [77] However, there is no consensus or standardized definition for evaluation of outcomes between studies [77]. While there are no studies comparing surgical management with placebo, some approaches appear to be more successful than others. Vestibuloplasty, where the vestibule is simply incised and re-approximated, has been noted to be ineffective. [77] Furthermore, there may be subsets of patients more likely to experience a benefit from vestibulectomy. Indications, risks, benefits, as well as the specific procedures utilized are described in the chapter on surgery of the vulva. Laser Few studies have been performed evaluating the utility of laser therapy in the treatment of vulvodynia. A retrospective study noted less pain with sexual intercourse among 24 of 37 women treated with pulsed laser therapy for vestibulodynia [78]. However, 35% of the patients in the study went on to have vestibulectomy for the control of symptoms [78]. Biofeedback therapy and physical therapy Due to the significant component of pelvic floor hypertonicity associated with vulvodynia, more often vestibulodynia, women should be assessed for pelvic floor dysfunction. Biofeedback and physical therapy are essential in treating both localized and generalized pain accompanied by myofascialrelated dysfunction as reviewed in the chapter on physical therapy. Psychotherapy Vulvodynia, like other chronic pain syndromes, has a significant emotional impact on the patient. Thus, a comprehensive treatment approach is imperative as sexual pain, no matter the cause, involves physical, psychological, and relationship components and benefits from sexual counseling and emotional support. Patients need assurance that referral for emotional therapy does not imply that the clinician has concluded the pain is not real. Rather, dialogue regarding a comprehensive treatment approach including counseling and psychological support can help allay fears that the patient may
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
1009
already have about their pain being psychological. Evaluation and management is covered in the section on psychosexual aspects of vulvar disease. Alternative medicine strategies Hypnotherapy Limited findings for hypnotherapy noted a significant decrease in pain associated with gynecologic examination and intercourse, as well as increased sexual satisfaction in nine patients [79,80]. Acupuncture Similarly, the use of acupuncture for vestibulodynia described a significant increase in positive quality-of-life measures and a significant decrease in negative quality-of-life measures [81]. The success for both hypnotherapy and acupuncture remains unclear given the lack of available evidence to date. Treatment summary Available data evaluating medical therapy for the treatment of vulvodynia suggest improvement with most proposed therapies. In the few placebo-controlled trials available, there are similar responses to both the treatment and placebo groups. Surgical therapy remains the most effective form of treatment for vestibulodynia, but has not been compared to placebo. Because less invasive options are typically beneficial, surgery is not generally used for initial treatment. An individualized, multidisciplinary approach should be considered to optimally address each underlying pain factor. Summary In summary, vulvodynia is a pain disorder that affects up to one in six women in the United States. The physical, psychosocial, and financial distress caused by chronic vulvar pain related to the diagnosis is significant for patients and their families. Diagnosis and treatment remains a frustrating endeavor for women's health providers due to the lack of understanding regarding the etiology and optimal treatment. It is unclear whether there is a significant difference between generalized unprovoked vulvodynia and vestibulodynia; however, most research has been done specifically pertaining to the latter. Proposed therapeutic measures are abundant; however, there is minimal evidence to suggest improvement in symptoms over placebo. The rapid resolution of vulvar pain is unusual, even with appropriate therapy. Thus, expectations for improvement should be addressed with the patient. Despite many published studies on the treatment of vulvodynia, management needs to be individualized. Future research should aim at identifying the underlying etiologies and pathogenesis as well as identifying the optimal multimodal approach to improve outcomes in women with this complex symptom constellation.
Practice points
Common e up to 16% in the general population Likely underdiagnosed: underreported and underrecognized Unclear etiology; likely multifactorial Unclear which is more common: generalized versus localized (majority of published studies look at vestibulodynia subset) Most studies evaluate treatment for localized provoked vulvodynia, whereas many fewer evaluate treatment for generalized vulvodynia There are few placebo-controlled trials available for treatments for vulvodynia Most of the placebo-controlled trials that exist suggest no benefit of treatment over placebo arms and thus observational studies that suggest benefit from particular modalities should be considered with some degree of caution
1010
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
Research agenda Placebo-controlled trials for all treatment modalities
References *[1] Moyal-Barracco M, Lynch PJ. 2003 ISSVD terminology and classification of vulvodynia: a historical perspective. J Reprod Med 2004 Oct;49(10):772e7. [2] Xie Y, Shi L, Xiong X, et al. Economic burden and quality of life of vulvodynia in the United States. Curr Med Res Opin 2012 Apr;28(4):601e8. [3] Harlow BL, Stewart EG. A population-based assessment of chronic unexplained vulvar pain: have we underestimated the prevalence of vulvodynia? J Am Med Womens Assoc 2003 Spring;58(2):82e8. [4] Goetsch MF. Vulvar vestibulitis: prevalence and historic features in a general gynecologic practice population. Am J Obstet Gynecol 1991 Jun;164(6 Pt 1):1609e14. discussion 1614e1616. *[5] Reed BD, Harlow SD, Sen A, et al. Prevalence and demographic characteristics of vulvodynia in a population-based sample. Am J Obstet Gynecol 2012 Feb;206(2):170.e1e9. [6] Bachmann GA, Rosen R, Pinn VW, et al. Vulvodynia: a state-of-the-art consensus on definitions, diagnosis and management. J Reprod Med 2006 Jun;51(6):447e56. [7] Harlow BL, Wise LA, Stewart EG. Prevalence and predictors of chronic lower genital tract discomfort. Am J Obstet Gynecol 2001 Sep;185(3):545e50. [8] Gardella B, Porru D, Ferdeghini F, et al. Insight into urogynecologic features of women with interstitial cystitis/painful bladder syndrome. Eur Urol 2008 Nov;54(5):1145e51. *[9] Reed BD, Harlow SD, Sen A, et al. Relationship between vulvodynia and chronic comorbid pain conditions. Obstet Gynecol 2012 Jul;120(1):145e51. [10] Dieleman JP, Kerklaan J, Huygen FJ, et al. Incidence rates and treatment of neuropathic pain conditions in the general population. Pain 2008 Jul 31;137(3):681e8. [11] Bohm-Starke N, Hilliges M, Falconer C, et al. Increased intraepithelial innervation in women with vulvar vestibulitis syndrome. Gynecol Obstet Invest 1998;46(4):256e60. [12] Bohm-Starke N, Hilliges M, Falconer C, et al. Neurochemical characterization of the vestibular nerves in women with vulvar vestibulitis syndrome. Gynecol Obstet Invest 1999;48(4):270e5. [13] Tympanidis P, Terenghi G, Dowd P. Increased innervation of the vulval vestibule in patients with vulvodynia. Br J Dermatol 2003 May;148(5):1021e7. [14] Witkin SS, Gerber S, Ledger WJ. Differential characterization of women with vulvar vestibulitis syndrome. Am J Obstet Gynecol 2002 Sep;187(3):589e94. [15] Ventolini G, Gygax SE, Adelson ME, et al. Vulvodynia and fungal association: a preliminary report. Med Hypotheses 2013 Aug;81(2):228e30. [16] Ramirez De Knott HM, McCormick TS, Do SO, et al. Cutaneous hypersensitivity to Candida albicans in idiopathic vulvodynia. Contact Dermat 2005 Oct;53(4):214e8. [17] Farage MA, Galask RP. Vulvar vestibulitis syndrome: a review. Eur J Obstet Gynecol Reprod Biol 2005 Nov 1;123(1):9e16. [18] Bornstein J, Livnat G, Stolar Z, et al. Pure versus complicated vulvar vestibulitis: a randomized trial of fluconazole treatment. Gynecol Obstet Invest 2000;50(3):194e7. [19] Bornstein J, Shapiro S, Rahat M, et al. Polymerase chain reaction search for viral etiology of vulvar vestibulitis syndrome. Am J Obstet Gynecol 1996 Jul;175(1):139e44. [20] Bergeron C, Moyal-Barracco M, Pelisse M, et al. Vulvar vestibulitis. Lack of evidence for a human papillomavirus etiology. J Reprod Med 1994 Dec;39(12):936e8. [21] Gaunt G, Good AE, McGovern RM, et al. Human papillomavirus in vulvar vestibulitis syndrome. J Reprod Med 2007 Jun; 52(6):485e9. [22] Marks TA, Shroyer KR, Markham NE, et al. A clinical, histologic, and DNA study of vulvodynia and its association with human papillomavirus. J Soc Gynecol Investig 1995 Jan-Feb;2(1):57e63. [23] Morin C, Bouchard C, Brisson J, et al. Human papillomaviruses and vulvar vestibulitis. Obstet Gynecol 2000 May;95(5): 683e7. *[24] Lundqvist EN, Hofer PA, Olofsson JI, et al. Is vulvar vestibulitis an inflammatory condition? A comparison of histological findings in affected and healthy women. Acta Derm Venereol 1997 Jul;77(4):319e22. [25] Eva LJ, Rolfe KJ, MacLean AB, et al. Is localized, provoked vulvodynia an inflammatory condition? J Reprod Med 2007 May; 52(5):379e84. [26] Gerber S, Bongiovanni AM, Ledger WJ, et al. Interleukin-1beta gene polymorphism in women with vulvar vestibulitis syndrome. Eur J Obstet Gynecol Reprod Biol 2003 Mar 26;107(1):74e7. [27] Gerber S, Bongiovanni AM, Ledger WJ, et al. A deficiency in interferon-alpha production in women with vulvar vestibulitis. Am J Obstet Gynecol 2002 Mar;186(3):361e4. [28] Jeremias J, Ledger WJ, Witkin SS. Interleukin 1 receptor antagonist gene polymorphism in women with vulvar vestibulitis. Am J Obstet Gynecol 2000 Feb;182(2):283e5. [29] Reed B, Harlow S, Legocki L, et al. Oral contraceptive use and risk of vulvodynia: a population-based longitudinal study. BJOG 2013 Dec;120(13):1678e84. [30] Greenstein A, Ben-Aroya Z, Fass O, et al. Vulvar vestibulitis syndrome and estrogen dose of oral contraceptive pills. J Sex Med 2007 Nov;4(6):1679e83.
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
1011
[31] Bazin S, Bouchard C, Brisson J, et al. Vulvar vestibulitis syndrome: an exploratory case-control study. Obstet Gynecol 1994 Jan;83(1):47e50. [32] Berglund AL, Nigaard L, Rylander E. Vulvar pain, sexual behavior and genital infections in a young population: a pilot study. Acta Obstet Gynecol Scand 2002 Aug;81(8):738e42. [33] Bouchard C, Brisson J, Fortier M, et al. Use of oral contraceptive pills and vulvar vestibulitis: a case-control study. Am J Epidemiol 2002 Aug 1;156(3):254e61. [34] Edgardh K, Abdelnoor M. Vulvar vestibulitis and risk factors: a population-based case-control study in Oslo. Acta Derm Venereol 2007;87(4):350e4. [35] Solomons CC, Melmed MH, Heitler SM. Calcium citrate for vulvar vestibulitis. A case report. J Reprod Med 1991 Dec; 36(12):879e82. [36] Harlow BL, Abenhaim HA, Vitonis AF, et al. Influence of dietary oxalates on the risk of adult-onset vulvodynia. J Reprod Med 2008 Mar;53(3):171e8. [37] Baggish MS, Sze EH, Johnson R. Urinary oxalate excretion and its role in vulvar pain syndrome. Am J Obstet Gynecol 1997 Sep;177(3):507e11. [38] Dalton VK, Haefner HK, Reed BD, et al. Victimization in patients with vulvar dysesthesia/vestibulodynia. Is there an increased prevalence? J Reprod Med 2002 Oct;47(10):829e34. [39] Harlow BL, Stewart EG. Adult-onset vulvodynia in relation to childhood violence victimization. Am J Epidemiol 2005 May 1;161(9):871e80. [40] Mascherpa F, Bogliatto F, Lynch PJ, et al. Vulvodynia as a possible somatization disorder. More than just an opinion. J Reprod Med 2007 Feb;52(2):107e10. [41] Reed BD, Haefner HK, Cantor L. Vulvar dysesthesia (vulvodynia). A follow-up study. J Reprod Med 2003 Jun;48(6):409e16. *[42] Reed BD, Haefner HK, Punch MR, et al. Psychosocial and sexual functioning in women with vulvodynia and chronic pelvic pain. A comparative evaluation. J Reprod Med 2000 Aug;45(8):624e32. [43] Lynch PJ. Vulvodynia as a somatoform disorder. J Reprod Med 2008 Jun;53(6):390e6. [44] Davis SN, Bergeron S, Binik YM, et al. Women with provoked vestibulodynia experience clinically significant reductions in pain regardless of treatment: results from a 2-year follow-up study. J Sex Med 2013 Sep 12;10(12):3080e7. [45] Rodriguez MA, Afari N, Buchwald DS. National Institute of Diabetes and Digestive and Kidney Diseases Working Group on Urological Chronic Pelvic Pain. Evidence for overlap between urological and nonurological unexplained clinical conditions. J Urol 2009 Nov;182(5):2123e31. [46] Zolnoun DA, Hartmann KE, Steege JF. Overnight 5% lidocaine ointment for treatment of vulvar vestibulitis. Obstet Gynecol 2003 Jul;102(1):84e7. *[47] Foster DC, Kotok MB, Huang LS, et al. Oral desipramine and topical lidocaine for vulvodynia: a randomized controlled trial. Obstet Gynecol 2010 Sep;116(3):583e93. [48] Danielsson I, Torstensson T, Brodda-Jansen G, et al. EMG biofeedback versus topical lidocaine gel: a randomized study for the treatment of women with vulvar vestibulitis. Acta Obstet Gynecol Scand 2006;85(11):1360e7. *[49] Haefner HK, Collins ME, Davis GD, et al. The vulvodynia guideline. J Low Genit Tract Dis 2005 Jan;9(1):40e51. [50] Nyirjesy P, Sobel JD, Weitz MV, et al. Cromolyn cream for recalcitrant idiopathic vulvar vestibulitis: results of a placebo controlled study. Sex Transm Infect 2001 Feb;77(1):53e7. [51] Murina F, Tassan P, Roberti P, et al. Treatment of vulvar vestibulitis with submucous infiltrations of methylprednisolone and lidocaine. An alternative approach. J Reprod Med 2001 Aug;46(8):713e6. [52] Steinberg AC, Oyama IA, Rejba AE, et al. Capsaicin for the treatment of vulvar vestibulitis. Am J Obstet Gynecol 2005 May; 192(5):1549e53. [53] Bornstein J, Tuma R, Farajun Y, et al. Topical nifedipine for the treatment of localized provoked vulvodynia: a placebocontrolled study. J Pain 2010 Dec;11(12):1403e9. [54] Walsh KE, Berman JR, Berman LA, et al. Safety and efficacy of topical nitroglycerin for treatment of vulvar pain in women with vulvodynia: a pilot study. J Gend Specif Med 2002 Jul-Aug;5(4):21e7. [55] Rogalski MJ, Kellogg-Spadt S, Hoffmann AR, et al. Retrospective chart review of vaginal diazepam suppository use in hightone pelvic floor dysfunction. Int Urogynecol J 2010 Jul;21(7):895e9. [56] Carrico DJ, Peters KM. Vaginal diazepam use with urogenital pain/pelvic floor dysfunction: serum diazepam levels and efficacy data. Urol Nurs 2011 SepeOct;31(5):279e84. 299. [57] Boardman LA, Cooper AS, Blais LR, et al. Topical gabapentin in the treatment of localized and generalized vulvodynia. Obstet Gynecol 2008 Sep;112(3):579e85. [58] Nyirjesy P, Lev-Sagie A, Mathew L, et al. Topical amitriptyline-baclofen cream for the treatment of provoked vestibulodynia. J Low Genit Tract Dis 2009;13(4):230e6. [59] Pagano R, Wong S. Use of amitriptyline cream in the management of entry dyspareunia due to provoked vestibulodynia. J Low Genit Tract Dis 2012 Oct;16(4):394e7. [60] Burrows LJ, Goldstsein AT. The treatment of vestibulodynia with topical estradiol and testosterone. J Sex Med 2013;1(1): 30e3. [61] Donders GG, Bellen G. Cream with cutaneous fibroblast lysate for the treatment of provoked vestibulodynia: a doubleblind randomized placebo-controlled crossover study. J Low Genit Tract Dis 2012 Oct;16(4):427e36. [62] Sindrup SH, Otto M, Finnerup NB, et al. Antidepressants in the treatment of neuropathic pain. Basic Clin Pharmacol Toxicol 2005 Jun;96(6):399e409. [63] Munday PE. Response to treatment in dysaesthetic vulvodynia. J Obstet Gynaecol 2001 Nov;21(6):610e3. [64] Reed BD, Caron AM, Gorenflo DW, et al. Treatment of vulvodynia with tricyclic antidepressants: efficacy and associated factors. J Low Genit Tract Dis 2006 Oct;10(4):245e51. *[65] Leo RJ, Dewani S. A systematic review of the utility of antidepressant pharmacotherapy in the treatment of vulvodynia pain. J Sex Med 2013 Oct;10(10):2497e505. [66] Dworkin RH, O'Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007 Dec 5;132(3):237e51.
1012
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
[67] Montejo-Gonzalez AL, Llorca G, Izquierdo JA, et al. SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther 1997 Fall; 23(3):176e94. [68] Jerome L. Pregabalin-induced remission in a 62-year-old woman with a 20-year history of vulvodynia. Pain Res Manag 2007 Autumn;12(3):212e4. [69] Jeon Y, Kim Y, Shim B, et al. A retrospective study of the management of vulvodynia. Korean J Urol 2013 Jan;54(1):48e52. [70] Meltzer-Brody SE, Zolnoun D, Steege JF, et al. Open-label trial of lamotrigine focusing on efficacy in vulvodynia. J Reprod Med 2009 Mar;54(3):171e8. [71] Ventolini G, Barhan S, Duke J. Vulvodynia, a step-wise therapeutic prospective cohort study. J Obstet Gynaecol 2009 Oct; 29(7):648e50. *[72] Leo RJ. A systematic review of the utility of anticonvulsant pharmacotherapy in the treatment of vulvodynia pain. J Sex Med 2013 Aug;10(8):2000e8. [73] Segal D, Tifheret H, Lazer S. Submucous infiltration of betamethasone and lidocaine in the treatment of vulvar vestibulitis. Eur J Obstet Gynecol Reprod Biol 2003 Mar 26;107(1):105e6. [74] Aoki KR. Review of a proposed mechanism for the antinociceptive action of botulinum toxin type A. Neurotoxicology 2005 Oct;26(5):785e93. [75] Petersen CD, Giraldi A, Lundvall L, et al. Botulinum toxin type A-a novel treatment for provoked vestibulodynia? Results from a randomized, placebo controlled, double blinded study. J Sex Med 2009 Sep;6(9):2523e37. [76] Farajun Y, Zarfati D, Abramov L, et al. Enoxaparin treatment for vulvodynia: a randomized controlled trial. Obstet Gynecol 2012 Sep;120(3):565e72. *[77] Tommola P, Unkila-Kallio L, Paavonen J. Surgical treatment of vulvar vestibulitis: a review. Acta Obstet Gynecol Scand 2010 Nov;89(11):1385e95. [78] Leclair CM, Goetsch MF, Lee KK, et al. KTP-nd:YAG laser therapy for the treatment of vestibulodynia: a follow-up study. J Reprod Med 2007 Jan;52(1):53e8. [79] Kandyba K, Binik YM. Hypnotherapy as a treatment for vulvar vestibulitis syndrome: a case report. J Sex Marital Ther 2003 MayeJun;29(3):237e42. [80] Pukall C, Kandyba K, Amsel R, et al. Effectiveness of hypnosis for the treatment of vulvar vestibulitis syndrome: a preliminary investigation. J Sex Med 2007 Mar;4(2):417e25. [81] Danielsson I, Sjoberg I, Ostman C. Acupuncture for the treatment of vulvar vestibulitis: a pilot study. Acta Obstet Gynecol Scand 2001 May;80(5):437e41.
Contents lists available at ScienceDirect
Best Practice & Research Clinical Obstetrics and Gynaecology journal homepage: www.elsevier.com/locate/bpobgyn
6
Vulvodynia Erin Eppsteiner, MD, Fellow Associate a, *, Lori Boardman, MD, ScM, Professor of Obstetrics and Gynecology b, 1, Colleen K. Stockdale, MD, MS, Clinical Associate Professor a, 2 a
Department of Obstetrics and Gynecology, 200 Hawkins Drive, University of Iowa, Iowa City, IA, USA University of Central Florida College of Medicine, 12201 Research Parkway, 3rd Floor, Orlando, FL 32816-0116, USA
b
Keywords: vulvodynia vestibulodynia vulvar pain dyspareunia
Vulvodynia is a complex disorder reported by up to 16% of women in the general population. While most patients describe it as burning, stinging, irritation, or rawness, it is underreported and underrecognized by providers. Vulvodynia is costly both economically and psychologically due to its negative impact on quality of life. Vulvodynia is a diagnosis of exclusion with unknown etiology and may involve multiple sources of pain in the same woman. Thus, there are no clinical or histopathologic criteria for the diagnosis other than consideration and careful evaluation to exclude other causes of pain. Successful therapy often requires a multidisciplinary approach with more than one therapeutic intervention to address the physical, psychological, psychosexual, and relationship components. © 2014 Elsevier Ltd. All rights reserved.
Introduction The International Society for the Study of Vulvovaginal Disease (ISSVD) most recently defined vulvodynia as “vulvar pain occurring in the absence of an underlying recognizable disease.” [1]. Vulvodynia is further classified based on the site of the pain, whether it is provoked, unprovoked, or mixed and subcategorized as generalized or localized.
* Corresponding author. Tel.: þ1 319 384 8685; Fax: þ1 319 384 8620. E-mail address: [email protected] (E. Eppsteiner). 1 Tel.: þ1 407 823 0500; Fax: þ1 407 823 1856. 2 Tel.: þ1 319 384 6849; Fax: þ1 319 384 8620.
http://dx.doi.org/10.1016/j.bpobgyn.2014.07.009 1521-6934/© 2014 Elsevier Ltd. All rights reserved.
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
1001
Vulvodynia significantly impacts patients' quality of life and can be the source of physical, psychosexual, and relationship distress for affected women. Similarly, clinicians experience frustration in diagnosing and treating vulvodynia in an efficient and effective manner. The cost of vulvodynia management in the United States is estimated to be $31 to $72 billion per year [2]. Unfortunately, there remains a relative paucity of research despite the impact on women and society. Epidemiology Among women living in the United States, the prevalence of vulvodynia has been estimated to range from 4% to 16% [3e6]. A clinic-based prevalence study identified 15% (of 210 women) with localized vulvodynia [4]. Half of the patients reported lifelong symptoms whereas a significant proportion of the remaining patients reported onset following childbirth [4]. Subsequently, a populationbased study found nearly 16% (of 4915 women) reported a 3-month history of vulvar pain [3]. Localized vulvodynia was confirmed in 78% who presented for clinical exam [3]. Symptoms were associated with younger age, earlier menarche, and pain with first tampon use [7]. White and African American women had similar prevalences, whereas Hispanic women were 80% more likely than either white or African American women to experience vulvar pain [3]. While 60% of women reporting vulvar pain sought treatment (the majority by at least three providers), the diagnosis remained elusive [3,7]. Similarly, a population-based study including >2200 women found that about half of women meeting vulvodynia criteria sought treatment for their symptoms and only 1.4% were diagnosed with vulvodynia [5]. Because vulvodynia is a diagnosis of exclusion, findings from epidemiologic studies without clinical confirmation should be interpreted with caution. Etiology While many theories regarding associated factors and vulvodynia have been suggested, evidence for the underlying etiology remains elusive. Embryology Vulvodynia has been associated with other chronic pain conditions including painful bladder, irritable bowel syndrome, and fibromyalgia [8,9]. Given the shared embryologic origin (urogenital sinus) for the lower genital tract, a unifying mechanism of pain development has been proposed. Neuropathic pain Perhaps the most compelling origin of vulvodynia is a neuropathic pain disorder. Neuropathic pain is defined by the International Association for the Study of Pain as a complex pain initiated by a primary lesion or dysfunction of the nervous system [10]. The pain described by patients with vulvodynia is similar in nature to that described by patients with neuropathic pain such as postherpetic neuralgia and diabetic neuropathy. Patients most often describe a burning pain which can be constant, but may be exacerbated by certain triggers. Studies suggest both central and peripheral responses to neuromodulating agents, further supporting this etiology. Additionally, patients with vulvodynia have an increase in number and caliber of nerves, specifically pain-sensing nociceptors, which may lend to increased sensitivity [11e13]. Infection Potential infectious etiologies have been investigated [14e16]. While Farage et al. reported that up to 80% of women with vulvodynia have a self-reported history of recurrent vulvovaginal candidiasis, Bornstein noted that treatment with fluconazole did not improve vulvar pain symptoms among 40 women with vulvodynia, several of whom had culture-proven vulvovaginal candidiasis [17,18].
1002
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
However, it is unclear whether symptoms were related to the topical therapies used for treatment or the candidal infection. The human papillomavirus (HPV) was also implicated as a factor in the development of vulvodynia [19]. However, subsequent studies have not demonstrated an association between HPV and vulvodynia [20e23]. Thus, HPV noted among women with vulvodynia is likely a reflection of the general prevalence rather than a true association. Inflammation Based on the presence of vulvar erythema, older terminology referred to vestibulitis, “-itis” signifying inflammation. This was initially corroborated by tissue samples of patients with vestibulodynia who were noted to have an inflammatory infiltrate. However, subsequent studies noted the presence of an inflammatory infiltrate in asymptomatic controls [24,25]. Thus, the presence of inflammation, either clinically or histologically, is not a diagnostic marker for vulvodynia. Genetics Genetic features may predispose women to the development of neuropathic pain. Specifically, allele 2 of interleukin 1 beta (IL-1 beta) receptor antagonist (an inflammatory mediator) may be associated with an exaggerated response to inflammation due to decreased ability to downregulate the inflammatory activity [14,26e28]. Hormonal influence Based largely on anecdotal evidence, vulvodynia was noted to occur in women with possible alterations in hormonal milieu, specifically resulting from hormonal birth control. While several studies have demonstrated an association with combined hormonal contraception and the risk of developing vulvodynia, other studies have not [29e34]. Dietary influences The association of dietary oxalates and vulvodynia was based on a single case report describing the complete relief of vulvodynia in a woman following a low-oxalate diet with calcium citrate supplementation [35]. Two subsequent case-controlled studies found no difference in oxalate excretion nor an association with vulvodynia [36,37]. Thus, dietary oxalate consumption is not currently recommended for the management of vulvodynia. Anatomic Pelvic floor dysfunction can be a predisposing or coexisting condition. While it remains unclear whether pelvic floor dysfunction is a result of chronic pain from vulvodynia or a precipitating factor, physical therapy and biofeedback can improve muscle tone and pain symptoms when present. Psychosocial Vulvodynia causes significant emotional and psychosocial distress in affected patients, and subsequently their families and their sexual partners. While it has been postulated that avoidance of intimacy may be due to an increased incidence of childhood physical or sexual abuse in women with vulvodynia, evidence remains contradictory [38e41]. Furthermore, women with vulvodynia were noted to share similar psychological characteristics to controls and have comparable marital satisfaction [42]. Regardless of which occurred first, pain or psychologic distress, targeted psychosocial therapy leads to improvement of pain for some patients [43].
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
1003
Prognosis A prospective study involving 239 women with provoked vestibulodynia noted significant improvement in pain ratings, sexual satisfaction, sexual function, and depressive symptoms (as assessed by Beck Depression Inventory) over 2 years, regardless of treatment modality [44]. While the most common treatments were physical therapy, sex/psychotherapy, and medical treatment, 41% received no treatment. The only single treatment with superior outcome was surgery; however, this treatment improved only depressive symptoms and did not affect pain [44]. Although this study is prognostically informational, it did not have the data to support the use of one treatment modality over another. Rather, this study supports the use of placebo-controlled trials to assess treatment outcomes beyond the apparent natural progression of provoked vestibulodynia. Diagnosis Women with vulvodynia present with varied complaints depending on the subtype of their disease. Most patients with vulvodynia complain of a burning or tearing pain which can be constant or intermittent, spontaneous (unprovoked) or provoked (i.e., with vaginal penetration during physical examination, sexual intercourse, or placement of a tampon.) Given that vulvodynia is a diagnosis of exclusion, careful history and physical examination to rule out other etiologies of pain is imperative. Patient history Patients presenting with vulvar pain should be queried regarding character and duration of symptoms; medical, psychosocial, and surgical history; sexual history; allergies; and previous treatments. One should specifically inquire about current products that patients are using (including both over-the-counter and prescribed topicals), as the vulvar skin is particularly sensitive to additives in commonly used hygiene products as well as to components of sanitary and laundry products. A menstrual history clarifies whether pain is associated with menses and whether the patient is in a hypoestrogenic state such as menopause. Contraception methods should be assessed as barrier protection can cause contact irritation, while some hormonal methods can contribute to atrophy. It should be noted whether the patient is sexually active, including number and gender of partners and whether lubricant, sex toys, or dilators are used. Risk of infection such as yeast should be assessed as symptoms can mimic those of vulvodynia. Regarding medical and psychosocial history, diagnoses such as irritable bowel syndrome, painful bladder syndrome, and depression have been associated with vulvodynia [9,45]. While history of physical or sexual abuse should be determined to assist with optimal patient management, childhood physical or sexual abuse should be queried as both have been found to be more prevalent in a population of women with vulvodynia [39]. Physical trauma or history of pelvic surgery (e.g., pelvic reconstruction, cystocele repair, rectocele repair, etc.) can contribute to the development of nerve injury and resultant pain. Thus, obstetric history including route of delivery, use of forceps/vacuum, birth weight, and resultant obstetrical trauma with mode of repair should be included. Finally, it should be noted whether the patient has been examined for these symptoms in the past and the outcomes from treatments rendered. Physical exam The physical examination should include an abdominopelvic exam with specific attention paid to vulvar findings. The vulvar exam should begin with visualization of the entire vulva. This includes inspection from the mons anteriorly to the perianal skin posteriorly and into the intertriginous zones lateral to the labia majora. Careful examination helps to assess for change in color, erythema, edema, mass, or lesion. Shaving and waxing, as well as piercings, should be noted as they can predispose the patient to folliculitis and further exacerbate symptoms. The absence of a normal hair pattern and normal vulvar architecture may otherwise be suggestive of vulvar dermatoses.
1004
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
Bilateral inguinal areas should be palpated to assess for lymphadenopathy. Further evaluation of the patient's pain requires palpation of the vulva. At this point, the patient should demonstrate by pointing to where the pain is most severe. Offering a mirror with the back of the examining table elevated can assist the patient and practitioner in locating her pain. The examiner should then use the cotton swab to assess for areas of point tenderness which would determine whether the pain is generalized or localized, provoked or unprovoked. Asking the patient if she has pain before palpation with the cotton swab can further elucidate if the pain is spontaneous (unprovoked). A single-finger palpation of the perineal muscles should be undertaken to assess for evidence of vaginismus. A bimanual examination may be performed if there is concern based on history that the symptoms may be caused by pain in the upper genital tract. Finally, as vulvar pain can be referred pain from other parts of the body, such as the back or hips, a musculoskeletal evaluation may be indicated. Further testing Additional testing should be based on the patient's history and clinical exam. We recommend a wet mount for microscopy, vaginal pH, and fungal culture. A biopsy is not necessary unless there is a focal lesion suspicious for neoplasia or there is concern for underlying pathology/dermatoses. Treatment Vulvodynia is often multifactorial in origin; thus, a multidisciplinary approach to treatment should be considered. The team of providers may involve sexual counselors, clinical psychologists, physical therapists, and pain specialists in addition to the primary treating provider. It is crucial to maintain communication among all involved treating providers to avoid duplication of therapy and optimize a cohesive treatment plan. It is critical to have a good working relationship with the patient. Any treatment approach should begin with a discussion including an explanation of the diagnosis and realistic treatment goals. A general guiding principle is to begin with those treatment options with the fewest side effects or potential complications. The patient should be counseled that follow-up is needed to evaluate treatment responses and adjust the therapeutic plan as needed to maximize pain reduction. The majority of therapeutic regimens for vulvodynia have been established based on expert opinion, clinical experience, and observational studies with no single best regimen identified. Few randomized controlled trials exist. Current modalities include vulvovaginal skin care guidelines; use of medical therapies including oral, topical, and injectable medications; biofeedback and physical therapy; psychosexual counseling; and surgical intervention, as well as complementary and alternative therapies. It is important to note that the majority of the research to date has focused on the treatment of vestibulodynia and less on the treatment of generalized vulvodynia. Additionally, modalities such as vestibulectomy do not apply to treatment of generalized vulvodynia. Skin care guidelines Products used on the vulva may incite contact irritation further contributing to vulvodynia. Thus, we recommend elimination of all potential irritants (Table 1). Additional recommendations include
Table 1 Common vulvar irritants. Perfumed laundry detergents Fabric softeners/dryer sheets Perfumed body soaps Feminine wipes Douches Pads and tampons with perfumes/avoid use of daily panty liner Topical medications
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
1005
cleansing the vulvar skin with warm water only and patting dry, use of white cotton underwear, and avoidance of tight-fitting clothing. The patient should be educated that lubrication is imperative for intercourse and encouraged to use plain unscented/unflavored silicone- or oil-based products that generally maintain their lubricating properties for longer than water-based products. The patient's household members and sexual partners should make similar changes regarding products in order to prevent cross contamination (from shared laundry) and continued irritation (from direct contact). A common barrier to implementing these changes is the patient report that they have “always used such methods and products” without prior difficulty. It is important to emphasize that product formulations as well as vulvar sensitivity can change over time. Thus, elimination of possible irritants is imperative for treating both localized and generalized vulvodynia. Clinicians should also consider elimination of prescription products and starting anew as patients can develop sensitivities to these products or the base in which they are prepared. Medical management Topical With all topical medications, it is helpful to use a mirror in the clinic setting and show the patient exactly how much and where to apply the medication to ensure they receive the desired effect and minimize local and systemic side effects. Some patients may develop worsening of discomfort with use of a topical medication, which may signify sensitivity to the medication and/or to the base in which it is prepared. As noted, ointments are better tolerated than creams due to additives, specifically drying agents, which tend to be present in cream preparations. If a patient develops sensitivity to multiple agents, evaluation may be warranted. Medication can then be compounded to avoid vehicles to which the patient is sensitive. Lidocaine The most commonly prescribed topical medication for the treatment of vestibulodynia is lidocaine (2e5%) in the form of a gel, cream, or ointment. It can be used as a palliative measure for sexual intercourse or it can be used to treat the skin. In the case of sexual intercourse, it should be applied 20e30 min prior to penetration or on an as-needed basis. Following application of 5% lidocaine ointment nightly for a mean of 7 weeks, 57% (of 61 patients) with vestibulodynia reported a significant (>50%) decrease in dyspareunia and 40% more women were able to have intercourse [46]. By contrast, a randomized, double-blinded, placebo-controlled trial compared the use of oral desipramine and topical 5% lidocaine cream as both monotherapy and combination therapy. The aim was to target both peripheral and central neuronal pathways, which would also potentially elucidate the origin of the neuropathic component of this diagnosis. All arms of the study, including the double placebo arm, demonstrated a decrease in vulvar pain. There was no significant difference between pain reduction in patients treated with placebo versus topical lidocaine monotherapy (33% vs. 20%) [47]. Yet another study compared the use of electromyographic biofeedback and topical lidocaine treatment over 4 months and found similar pain improvement in both groups [48]. The side effects of lidocaine include burning sensation at the site of application and toxicity which can be minimized by use of the smallest effective dose. Lidocaine 5% ointment (or 2% jelly) is most commonly prescribed for application 30 min before sexual activity [49]. Topical use of benzocaine and diphenhydramine should be avoided due to potential sensitization and irritation. Cromolyn Despite a case series demonstrating benefit, a randomized double-blind placebo-controlled study found cromolyn 4% cream to be no more effective than placebo in symptom reduction in women considered to have a possible allergic etiology of vestibulodynia [50]. Capsaicin Although observational studies demonstrated moderate improvement in dyspareunia in the majority of patients with vestibulodynia applying capsaicin >four times daily, treatment is often
1006
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
discontinued due to intolerance/discomfort with local application. This is not surprising given that capsaicin is the spicy element in hot chili peppers. Moreover, almost all patients who completed treatment required use of topical lidocaine or narcotic pain medication prior to the application of capsaicin and therefore it is unclear how much of the desired effect is attributed to capsaicin use [51,52]. Nifedipine While application of topical nifedipine has been shown to be successful in treating chronic anal fissure, a double-blind placebo-controlled trial demonstrated no difference in improvement in pain in women with vestibulodynia between the treatment and placebo groups (mean pain intensity improved in all arms of the study) [53]. Nitroglycerin Similar to nifedipine, nitroglycerine has demonstrated benefit for treating chronic anal fissure. A small prospective cohort study found 91% (of 34 women) with vulvodynia with introital dyspareunia noted improvement in overall pain following topical application of 0.2% nitroglycerine cream [54]. However, side effects including headaches, lightheadedness, dizziness, or fainting limit its use in clinical practice. Diazepam Due to its use in treatment of muscle spasm, observational studies primarily from the urology literature have evaluated the effect of vaginal diazepam on pain associated with pelvic floor dysfunction/hypertonicity [55,56]. While observational findings have suggested some improvement in a subgroup of women with vulvodynia, serum levels are similar to levels with systemic use, which raises concern for development of tolerance and substance dependence [56]. Gabapentin Based on success following oral gabapentin for neuropathic pain conditions and limited clinical observation with its use for vulvodynia (generalized and localized), the efficacy and tolerability of topical gabapentin were retrospectively evaluated. Twenty-eight (of 35 women with vulvodynia) demonstrated at least 50% improvement in pain scores. Furthermore, topical application was well tolerated [57]. Amitriptyline/baclofen Combined amitriptyline 2%, baclofen 2% cream was evaluated in a retrospective review of 38 women with vestibulodynia refractory to other medical treatment. Of this cohort, 71% identified a response of at least 30%, while 53% reported >60% improvement in dyspareunia [58]. Subsequently, the application of topical 2% amitriptyline twice daily was evaluated as a monotherapy in a prospective cohort of women with vestibulodynia over 3 months [59]. Fifty-six percent (of 150 patients) reported improvement, 10% of whom reported complete resolution of pain and pain-free intercourse [59]. Estrogen While an association between the use of combined hormonal contraceptives and vulvodynia remains controversial, a recent retrospective review of 50 premenopausal women using combined hormonal contraceptives with secondary vestibulodynia reported improvement in posttreatment pain scores following discontinuation of their medication and local application of topical estradiol and testosterone twice daily for an average treatment duration of 20 weeks [60]. Fibroblast lysate A recent crossover study evaluated the use of fibroblast lysate cream for treatment of vestibulodynia in 30 patients. There was a statistically significant (though clinically modest) decrease in erythema and dyspareunia with treatment over placebo [61]. Other topicals Topical steroids, progesterone, and antifungals have not been shown to be effective in the treatment of vulvodynia.
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
1007
Oral medications Antidepressants Antidepressant medications have been successfully used in the treatment of various chronic pain syndromes, not only for effects on depression which can accompany chronic pain, but also for effects on pain. Antidepressants have been shown to be effective in patients with and without depressive symptoms [62]. Additionally, patients report improvement in symptoms with low numbers needed to be treated [62]. As noted previously, a double-blind, placebo-controlled, four-arm study using oral desipramine and topical 5% lidocaine cream as both monotherapy and combination therapy was conducted. All arms of the study, including the double-placebo arm, demonstrated a decrease in vulvar pain. There was no significant difference between pain reduction in patients treated with placebo versus oral desipramine (33% vs. 24%) [47]. A cohort study noted at least 50% improvement among 87% participants following combined tricyclic antidepressant (TCA) combined with counseling and support for vulvodynia of which 47% of 32 patients reported complete relief [63]. However, the proportion of improvement attributed to the TCA is unclear given the use of combined therapy. Subsequently, in a prospective cohort evaluating the TCA effectiveness, 59% (of 83 women) using a TCA for vulvodynia improved by >50% in contrast to 38% (of 79 women) not using a TCA [64]. While antidepressant medications have not been directly compared, TCAs are the most studied and appear to be more effective than other classes. In reports of previously failed therapy with selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), TCAs were found to be successful in reducing vulvar pain [65]. There is evidence for the use of SNRIs in neuropathic pain, although this has not been studied in vulvodynia [66]. SSRIs are generally less effective than TCAs for pain, but the side-effect profile of SSRIs are generally better than the notorious anticholinergic side effects of TCAs. It is recommended that low doses be used initially and titrated based on patient tolerance and response. Common anticholinergic side effects with TCA use are dry mouth, blurred vision, constipation, drowsiness, and increased appetite. Many women will experience a modest weight gain with TCAs. Most side effects are short term and resolve once the patient is stabilized on therapy. It has also been reported that some antidepressants, typically the SSRIs and SNRIs, can have negative effects on sexual function [67]. This is not typically noted with the TCAs. Although this has not been well described in the vulvodynia literature, it warrants mention given that patients with vulvodynia are often struggling with poor sexual function and comorbid psychosexual conditions. Thus, disclosure is important and titrating adequate doses for pain control can be limited by patient tolerance of side effects. Antiepileptics In patients who cannot tolerate adequate doses of TCAs or report inadequate relief of vulvodynia, anticonvulsant medications are often considered. Antiepileptics are Food and Drug Administration (FDA) approved for treating other forms of neuropathic pain. Gabapentin has been the utilized and most studied anticonvulsant for all types of vulvodynia [49]. Other anticonvulsants useful for vulvodynia treatment in cohort studies include pregabalin, lamotrigine, and carbamazepine [68e71]. Similar to studies of other therapies for vulvodynia, randomized trials or comparative studies are not available. The side effects of gabapentin are similar to those noted with antidepressants (e.g., mild cognitive impairment, weight gain, and increased appetite), but are thought to be less severe. Generally, improvement in vulvodynia pain was noted following the use of topical and oral gabapentin as well as oral lamotrigine in observational studies [72]. However, whether the improvement in pain occurred because of therapy or represented a regression to the mean was questioned. No randomized trials studying the effectiveness of gabapentin against placebo have been performed. When prescribing antidepressant or anticonvulsant medications, it is important to attempt use for several weeks (e.g., 4e8 weeks) before determining the full effect. When discontinuing after stable use, it is important to taper the dose, as abrupt discontinuation can have significant effects similar to alcohol or benzodiazepine withdrawal including insomnia, restlessness, agitation, anxiety, and confusion.
1008
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
Injections Corticosteroid Thought to be due to anti-inflammatory effects, submucosal injection of corticosteroid has been reportedly successful at improving vulvar pain associated with vestibulodynia [51,73]. Botulinum toxin A Suggested following successful use in other pain syndromes, botulinum toxin may have a specific pain-modulating effect in addition to its paralytic effects [74]. While several small, open-label studies have shown improvement in symptoms with botulinum toxin at doses of 20e100 units, the only randomized, double-blinded, placebo-controlled trial demonstrated no improvement with 20 units over placebo in 64 women with vulvodynia [75]. Other injections A recent placebo-controlled study was undertaken to evaluate enoxaparin based on the increased presence of heparanase in the vestibule of women with vestibulodynia. While modest, 15 of 20 enoxaparin-treated women reported >20% reduction in pain compared to five of 18 women in the placebo group [76]. Vestibulectomy Surgical intervention is not generally considered first-line therapy due to the desire to pursue less invasive options. Thus, patients proceeding with surgical therapy have often failed a number of other medical therapies or interventions. Vestibulectomy is reserved for patients with vestibulodynia and not those with generalized unprovoked vulvodynia. A critical review of the literature to date suggests that vestibulectomy is successful in 60e90% of cases, whereas other nonsurgical therapies are 40e80% effective. [77] However, there is no consensus or standardized definition for evaluation of outcomes between studies [77]. While there are no studies comparing surgical management with placebo, some approaches appear to be more successful than others. Vestibuloplasty, where the vestibule is simply incised and re-approximated, has been noted to be ineffective. [77] Furthermore, there may be subsets of patients more likely to experience a benefit from vestibulectomy. Indications, risks, benefits, as well as the specific procedures utilized are described in the chapter on surgery of the vulva. Laser Few studies have been performed evaluating the utility of laser therapy in the treatment of vulvodynia. A retrospective study noted less pain with sexual intercourse among 24 of 37 women treated with pulsed laser therapy for vestibulodynia [78]. However, 35% of the patients in the study went on to have vestibulectomy for the control of symptoms [78]. Biofeedback therapy and physical therapy Due to the significant component of pelvic floor hypertonicity associated with vulvodynia, more often vestibulodynia, women should be assessed for pelvic floor dysfunction. Biofeedback and physical therapy are essential in treating both localized and generalized pain accompanied by myofascialrelated dysfunction as reviewed in the chapter on physical therapy. Psychotherapy Vulvodynia, like other chronic pain syndromes, has a significant emotional impact on the patient. Thus, a comprehensive treatment approach is imperative as sexual pain, no matter the cause, involves physical, psychological, and relationship components and benefits from sexual counseling and emotional support. Patients need assurance that referral for emotional therapy does not imply that the clinician has concluded the pain is not real. Rather, dialogue regarding a comprehensive treatment approach including counseling and psychological support can help allay fears that the patient may
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
1009
already have about their pain being psychological. Evaluation and management is covered in the section on psychosexual aspects of vulvar disease. Alternative medicine strategies Hypnotherapy Limited findings for hypnotherapy noted a significant decrease in pain associated with gynecologic examination and intercourse, as well as increased sexual satisfaction in nine patients [79,80]. Acupuncture Similarly, the use of acupuncture for vestibulodynia described a significant increase in positive quality-of-life measures and a significant decrease in negative quality-of-life measures [81]. The success for both hypnotherapy and acupuncture remains unclear given the lack of available evidence to date. Treatment summary Available data evaluating medical therapy for the treatment of vulvodynia suggest improvement with most proposed therapies. In the few placebo-controlled trials available, there are similar responses to both the treatment and placebo groups. Surgical therapy remains the most effective form of treatment for vestibulodynia, but has not been compared to placebo. Because less invasive options are typically beneficial, surgery is not generally used for initial treatment. An individualized, multidisciplinary approach should be considered to optimally address each underlying pain factor. Summary In summary, vulvodynia is a pain disorder that affects up to one in six women in the United States. The physical, psychosocial, and financial distress caused by chronic vulvar pain related to the diagnosis is significant for patients and their families. Diagnosis and treatment remains a frustrating endeavor for women's health providers due to the lack of understanding regarding the etiology and optimal treatment. It is unclear whether there is a significant difference between generalized unprovoked vulvodynia and vestibulodynia; however, most research has been done specifically pertaining to the latter. Proposed therapeutic measures are abundant; however, there is minimal evidence to suggest improvement in symptoms over placebo. The rapid resolution of vulvar pain is unusual, even with appropriate therapy. Thus, expectations for improvement should be addressed with the patient. Despite many published studies on the treatment of vulvodynia, management needs to be individualized. Future research should aim at identifying the underlying etiologies and pathogenesis as well as identifying the optimal multimodal approach to improve outcomes in women with this complex symptom constellation.
Practice points
Common e up to 16% in the general population Likely underdiagnosed: underreported and underrecognized Unclear etiology; likely multifactorial Unclear which is more common: generalized versus localized (majority of published studies look at vestibulodynia subset) Most studies evaluate treatment for localized provoked vulvodynia, whereas many fewer evaluate treatment for generalized vulvodynia There are few placebo-controlled trials available for treatments for vulvodynia Most of the placebo-controlled trials that exist suggest no benefit of treatment over placebo arms and thus observational studies that suggest benefit from particular modalities should be considered with some degree of caution
1010
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
Research agenda Placebo-controlled trials for all treatment modalities
References *[1] Moyal-Barracco M, Lynch PJ. 2003 ISSVD terminology and classification of vulvodynia: a historical perspective. J Reprod Med 2004 Oct;49(10):772e7. [2] Xie Y, Shi L, Xiong X, et al. Economic burden and quality of life of vulvodynia in the United States. Curr Med Res Opin 2012 Apr;28(4):601e8. [3] Harlow BL, Stewart EG. A population-based assessment of chronic unexplained vulvar pain: have we underestimated the prevalence of vulvodynia? J Am Med Womens Assoc 2003 Spring;58(2):82e8. [4] Goetsch MF. Vulvar vestibulitis: prevalence and historic features in a general gynecologic practice population. Am J Obstet Gynecol 1991 Jun;164(6 Pt 1):1609e14. discussion 1614e1616. *[5] Reed BD, Harlow SD, Sen A, et al. Prevalence and demographic characteristics of vulvodynia in a population-based sample. Am J Obstet Gynecol 2012 Feb;206(2):170.e1e9. [6] Bachmann GA, Rosen R, Pinn VW, et al. Vulvodynia: a state-of-the-art consensus on definitions, diagnosis and management. J Reprod Med 2006 Jun;51(6):447e56. [7] Harlow BL, Wise LA, Stewart EG. Prevalence and predictors of chronic lower genital tract discomfort. Am J Obstet Gynecol 2001 Sep;185(3):545e50. [8] Gardella B, Porru D, Ferdeghini F, et al. Insight into urogynecologic features of women with interstitial cystitis/painful bladder syndrome. Eur Urol 2008 Nov;54(5):1145e51. *[9] Reed BD, Harlow SD, Sen A, et al. Relationship between vulvodynia and chronic comorbid pain conditions. Obstet Gynecol 2012 Jul;120(1):145e51. [10] Dieleman JP, Kerklaan J, Huygen FJ, et al. Incidence rates and treatment of neuropathic pain conditions in the general population. Pain 2008 Jul 31;137(3):681e8. [11] Bohm-Starke N, Hilliges M, Falconer C, et al. Increased intraepithelial innervation in women with vulvar vestibulitis syndrome. Gynecol Obstet Invest 1998;46(4):256e60. [12] Bohm-Starke N, Hilliges M, Falconer C, et al. Neurochemical characterization of the vestibular nerves in women with vulvar vestibulitis syndrome. Gynecol Obstet Invest 1999;48(4):270e5. [13] Tympanidis P, Terenghi G, Dowd P. Increased innervation of the vulval vestibule in patients with vulvodynia. Br J Dermatol 2003 May;148(5):1021e7. [14] Witkin SS, Gerber S, Ledger WJ. Differential characterization of women with vulvar vestibulitis syndrome. Am J Obstet Gynecol 2002 Sep;187(3):589e94. [15] Ventolini G, Gygax SE, Adelson ME, et al. Vulvodynia and fungal association: a preliminary report. Med Hypotheses 2013 Aug;81(2):228e30. [16] Ramirez De Knott HM, McCormick TS, Do SO, et al. Cutaneous hypersensitivity to Candida albicans in idiopathic vulvodynia. Contact Dermat 2005 Oct;53(4):214e8. [17] Farage MA, Galask RP. Vulvar vestibulitis syndrome: a review. Eur J Obstet Gynecol Reprod Biol 2005 Nov 1;123(1):9e16. [18] Bornstein J, Livnat G, Stolar Z, et al. Pure versus complicated vulvar vestibulitis: a randomized trial of fluconazole treatment. Gynecol Obstet Invest 2000;50(3):194e7. [19] Bornstein J, Shapiro S, Rahat M, et al. Polymerase chain reaction search for viral etiology of vulvar vestibulitis syndrome. Am J Obstet Gynecol 1996 Jul;175(1):139e44. [20] Bergeron C, Moyal-Barracco M, Pelisse M, et al. Vulvar vestibulitis. Lack of evidence for a human papillomavirus etiology. J Reprod Med 1994 Dec;39(12):936e8. [21] Gaunt G, Good AE, McGovern RM, et al. Human papillomavirus in vulvar vestibulitis syndrome. J Reprod Med 2007 Jun; 52(6):485e9. [22] Marks TA, Shroyer KR, Markham NE, et al. A clinical, histologic, and DNA study of vulvodynia and its association with human papillomavirus. J Soc Gynecol Investig 1995 Jan-Feb;2(1):57e63. [23] Morin C, Bouchard C, Brisson J, et al. Human papillomaviruses and vulvar vestibulitis. Obstet Gynecol 2000 May;95(5): 683e7. *[24] Lundqvist EN, Hofer PA, Olofsson JI, et al. Is vulvar vestibulitis an inflammatory condition? A comparison of histological findings in affected and healthy women. Acta Derm Venereol 1997 Jul;77(4):319e22. [25] Eva LJ, Rolfe KJ, MacLean AB, et al. Is localized, provoked vulvodynia an inflammatory condition? J Reprod Med 2007 May; 52(5):379e84. [26] Gerber S, Bongiovanni AM, Ledger WJ, et al. Interleukin-1beta gene polymorphism in women with vulvar vestibulitis syndrome. Eur J Obstet Gynecol Reprod Biol 2003 Mar 26;107(1):74e7. [27] Gerber S, Bongiovanni AM, Ledger WJ, et al. A deficiency in interferon-alpha production in women with vulvar vestibulitis. Am J Obstet Gynecol 2002 Mar;186(3):361e4. [28] Jeremias J, Ledger WJ, Witkin SS. Interleukin 1 receptor antagonist gene polymorphism in women with vulvar vestibulitis. Am J Obstet Gynecol 2000 Feb;182(2):283e5. [29] Reed B, Harlow S, Legocki L, et al. Oral contraceptive use and risk of vulvodynia: a population-based longitudinal study. BJOG 2013 Dec;120(13):1678e84. [30] Greenstein A, Ben-Aroya Z, Fass O, et al. Vulvar vestibulitis syndrome and estrogen dose of oral contraceptive pills. J Sex Med 2007 Nov;4(6):1679e83.
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
1011
[31] Bazin S, Bouchard C, Brisson J, et al. Vulvar vestibulitis syndrome: an exploratory case-control study. Obstet Gynecol 1994 Jan;83(1):47e50. [32] Berglund AL, Nigaard L, Rylander E. Vulvar pain, sexual behavior and genital infections in a young population: a pilot study. Acta Obstet Gynecol Scand 2002 Aug;81(8):738e42. [33] Bouchard C, Brisson J, Fortier M, et al. Use of oral contraceptive pills and vulvar vestibulitis: a case-control study. Am J Epidemiol 2002 Aug 1;156(3):254e61. [34] Edgardh K, Abdelnoor M. Vulvar vestibulitis and risk factors: a population-based case-control study in Oslo. Acta Derm Venereol 2007;87(4):350e4. [35] Solomons CC, Melmed MH, Heitler SM. Calcium citrate for vulvar vestibulitis. A case report. J Reprod Med 1991 Dec; 36(12):879e82. [36] Harlow BL, Abenhaim HA, Vitonis AF, et al. Influence of dietary oxalates on the risk of adult-onset vulvodynia. J Reprod Med 2008 Mar;53(3):171e8. [37] Baggish MS, Sze EH, Johnson R. Urinary oxalate excretion and its role in vulvar pain syndrome. Am J Obstet Gynecol 1997 Sep;177(3):507e11. [38] Dalton VK, Haefner HK, Reed BD, et al. Victimization in patients with vulvar dysesthesia/vestibulodynia. Is there an increased prevalence? J Reprod Med 2002 Oct;47(10):829e34. [39] Harlow BL, Stewart EG. Adult-onset vulvodynia in relation to childhood violence victimization. Am J Epidemiol 2005 May 1;161(9):871e80. [40] Mascherpa F, Bogliatto F, Lynch PJ, et al. Vulvodynia as a possible somatization disorder. More than just an opinion. J Reprod Med 2007 Feb;52(2):107e10. [41] Reed BD, Haefner HK, Cantor L. Vulvar dysesthesia (vulvodynia). A follow-up study. J Reprod Med 2003 Jun;48(6):409e16. *[42] Reed BD, Haefner HK, Punch MR, et al. Psychosocial and sexual functioning in women with vulvodynia and chronic pelvic pain. A comparative evaluation. J Reprod Med 2000 Aug;45(8):624e32. [43] Lynch PJ. Vulvodynia as a somatoform disorder. J Reprod Med 2008 Jun;53(6):390e6. [44] Davis SN, Bergeron S, Binik YM, et al. Women with provoked vestibulodynia experience clinically significant reductions in pain regardless of treatment: results from a 2-year follow-up study. J Sex Med 2013 Sep 12;10(12):3080e7. [45] Rodriguez MA, Afari N, Buchwald DS. National Institute of Diabetes and Digestive and Kidney Diseases Working Group on Urological Chronic Pelvic Pain. Evidence for overlap between urological and nonurological unexplained clinical conditions. J Urol 2009 Nov;182(5):2123e31. [46] Zolnoun DA, Hartmann KE, Steege JF. Overnight 5% lidocaine ointment for treatment of vulvar vestibulitis. Obstet Gynecol 2003 Jul;102(1):84e7. *[47] Foster DC, Kotok MB, Huang LS, et al. Oral desipramine and topical lidocaine for vulvodynia: a randomized controlled trial. Obstet Gynecol 2010 Sep;116(3):583e93. [48] Danielsson I, Torstensson T, Brodda-Jansen G, et al. EMG biofeedback versus topical lidocaine gel: a randomized study for the treatment of women with vulvar vestibulitis. Acta Obstet Gynecol Scand 2006;85(11):1360e7. *[49] Haefner HK, Collins ME, Davis GD, et al. The vulvodynia guideline. J Low Genit Tract Dis 2005 Jan;9(1):40e51. [50] Nyirjesy P, Sobel JD, Weitz MV, et al. Cromolyn cream for recalcitrant idiopathic vulvar vestibulitis: results of a placebo controlled study. Sex Transm Infect 2001 Feb;77(1):53e7. [51] Murina F, Tassan P, Roberti P, et al. Treatment of vulvar vestibulitis with submucous infiltrations of methylprednisolone and lidocaine. An alternative approach. J Reprod Med 2001 Aug;46(8):713e6. [52] Steinberg AC, Oyama IA, Rejba AE, et al. Capsaicin for the treatment of vulvar vestibulitis. Am J Obstet Gynecol 2005 May; 192(5):1549e53. [53] Bornstein J, Tuma R, Farajun Y, et al. Topical nifedipine for the treatment of localized provoked vulvodynia: a placebocontrolled study. J Pain 2010 Dec;11(12):1403e9. [54] Walsh KE, Berman JR, Berman LA, et al. Safety and efficacy of topical nitroglycerin for treatment of vulvar pain in women with vulvodynia: a pilot study. J Gend Specif Med 2002 Jul-Aug;5(4):21e7. [55] Rogalski MJ, Kellogg-Spadt S, Hoffmann AR, et al. Retrospective chart review of vaginal diazepam suppository use in hightone pelvic floor dysfunction. Int Urogynecol J 2010 Jul;21(7):895e9. [56] Carrico DJ, Peters KM. Vaginal diazepam use with urogenital pain/pelvic floor dysfunction: serum diazepam levels and efficacy data. Urol Nurs 2011 SepeOct;31(5):279e84. 299. [57] Boardman LA, Cooper AS, Blais LR, et al. Topical gabapentin in the treatment of localized and generalized vulvodynia. Obstet Gynecol 2008 Sep;112(3):579e85. [58] Nyirjesy P, Lev-Sagie A, Mathew L, et al. Topical amitriptyline-baclofen cream for the treatment of provoked vestibulodynia. J Low Genit Tract Dis 2009;13(4):230e6. [59] Pagano R, Wong S. Use of amitriptyline cream in the management of entry dyspareunia due to provoked vestibulodynia. J Low Genit Tract Dis 2012 Oct;16(4):394e7. [60] Burrows LJ, Goldstsein AT. The treatment of vestibulodynia with topical estradiol and testosterone. J Sex Med 2013;1(1): 30e3. [61] Donders GG, Bellen G. Cream with cutaneous fibroblast lysate for the treatment of provoked vestibulodynia: a doubleblind randomized placebo-controlled crossover study. J Low Genit Tract Dis 2012 Oct;16(4):427e36. [62] Sindrup SH, Otto M, Finnerup NB, et al. Antidepressants in the treatment of neuropathic pain. Basic Clin Pharmacol Toxicol 2005 Jun;96(6):399e409. [63] Munday PE. Response to treatment in dysaesthetic vulvodynia. J Obstet Gynaecol 2001 Nov;21(6):610e3. [64] Reed BD, Caron AM, Gorenflo DW, et al. Treatment of vulvodynia with tricyclic antidepressants: efficacy and associated factors. J Low Genit Tract Dis 2006 Oct;10(4):245e51. *[65] Leo RJ, Dewani S. A systematic review of the utility of antidepressant pharmacotherapy in the treatment of vulvodynia pain. J Sex Med 2013 Oct;10(10):2497e505. [66] Dworkin RH, O'Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007 Dec 5;132(3):237e51.
1012
E. Eppsteiner et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 1000e1012
[67] Montejo-Gonzalez AL, Llorca G, Izquierdo JA, et al. SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther 1997 Fall; 23(3):176e94. [68] Jerome L. Pregabalin-induced remission in a 62-year-old woman with a 20-year history of vulvodynia. Pain Res Manag 2007 Autumn;12(3):212e4. [69] Jeon Y, Kim Y, Shim B, et al. A retrospective study of the management of vulvodynia. Korean J Urol 2013 Jan;54(1):48e52. [70] Meltzer-Brody SE, Zolnoun D, Steege JF, et al. Open-label trial of lamotrigine focusing on efficacy in vulvodynia. J Reprod Med 2009 Mar;54(3):171e8. [71] Ventolini G, Barhan S, Duke J. Vulvodynia, a step-wise therapeutic prospective cohort study. J Obstet Gynaecol 2009 Oct; 29(7):648e50. *[72] Leo RJ. A systematic review of the utility of anticonvulsant pharmacotherapy in the treatment of vulvodynia pain. J Sex Med 2013 Aug;10(8):2000e8. [73] Segal D, Tifheret H, Lazer S. Submucous infiltration of betamethasone and lidocaine in the treatment of vulvar vestibulitis. Eur J Obstet Gynecol Reprod Biol 2003 Mar 26;107(1):105e6. [74] Aoki KR. Review of a proposed mechanism for the antinociceptive action of botulinum toxin type A. Neurotoxicology 2005 Oct;26(5):785e93. [75] Petersen CD, Giraldi A, Lundvall L, et al. Botulinum toxin type A-a novel treatment for provoked vestibulodynia? Results from a randomized, placebo controlled, double blinded study. J Sex Med 2009 Sep;6(9):2523e37. [76] Farajun Y, Zarfati D, Abramov L, et al. Enoxaparin treatment for vulvodynia: a randomized controlled trial. Obstet Gynecol 2012 Sep;120(3):565e72. *[77] Tommola P, Unkila-Kallio L, Paavonen J. Surgical treatment of vulvar vestibulitis: a review. Acta Obstet Gynecol Scand 2010 Nov;89(11):1385e95. [78] Leclair CM, Goetsch MF, Lee KK, et al. KTP-nd:YAG laser therapy for the treatment of vestibulodynia: a follow-up study. J Reprod Med 2007 Jan;52(1):53e8. [79] Kandyba K, Binik YM. Hypnotherapy as a treatment for vulvar vestibulitis syndrome: a case report. J Sex Marital Ther 2003 MayeJun;29(3):237e42. [80] Pukall C, Kandyba K, Amsel R, et al. Effectiveness of hypnosis for the treatment of vulvar vestibulitis syndrome: a preliminary investigation. J Sex Med 2007 Mar;4(2):417e25. [81] Danielsson I, Sjoberg I, Ostman C. Acupuncture for the treatment of vulvar vestibulitis: a pilot study. Acta Obstet Gynecol Scand 2001 May;80(5):437e41.