1 Introduction

Vulvar conditions are common in women at every stage of their adult life cycle. However, depending on the age of the woman, there are more common ones seen at different points in the age spectrum. For reproductive-aged women, infections such as vulvar herpes and candida will often be seen. In the menopausal women, the genitourinary syndrome of menopause (formerly referred to as vulvovaginal atrophy) is typically the presenting complaint when there are vulvar complaints. In the postmenopausal age group, vulvar intraepithelial neoplasia increases in prevalence. Vulvodynia, a chronic pain condition, is a vulvar condition that occurs throughout the life cycle of the female. Unfortunately, this pain condition continues to be elusive in regard to both etiology and treatment. Treatment of infection, atrophy, and dysplasia usually follows evidence-based interventions that effectively treat the vulvar condition. On the other hand, clinicians caring for women with vulvodynia have utilized several pharmacologic interventions for management with varying degrees of efficacy and safety. This chapter presents an update on the medical treatment of vulvar disease, with an emphasis on the pharmacologic interventions for vulvodynia, since this is the one area that there remain many unanswered questions.

2 Vulvar Infections

Candidiasis is the most common vulvovaginal infection, affecting 75% of all women with at least one episode during their lifetimes [1]. It typically presents with patient symptoms of vulvar pruritus, irritation, dysuria, and dyspareunia. Women may also report redness of the vulvar area and a white, curd-like discharge at the introital area. Although candida is the most common agent for vulvar infection, other sexually transmitted diseases that affect the vulva are also seen. The Center for Disease Control (CDC) classification for vulvovaginal infections is shown in Table 6.1 [2].

Table 6.1 CDC classifications for vulvar and/or vaginal infections
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3 Genitourinary Syndrome of Menopause

With the loss of estrogen due to ovarian follicular depletion, a frequent condition in menopausal women that affects the vulva in addition to the vagina and lower genital tract is the genitourinary syndrome of menopause (GSM). Formerly referred to as vulvovaginal atrophy, GSM nomenclature was recently adopted since this condition includes adverse changes to not only the vulva and vagina but also the urethra, bladder, and lower pelvis [3]. Vulvar symptoms include genital dryness, burning, entry dyspareunia, and irritation, as well as decreased lubrication, pain with intercourse, urinary urgency, dysuria, and recurring urinary tract infection.

4 Vulvar Dermatoses

Chronic vulvar dermatoses, although occurring in all age groups, are most frequently seen in postmenopausal women. However, dermatoses in menopausal women occur less frequently than GSM. Of the vulvar dermatoses, lichen sclerosus (LS) is the one most commonly seen. LS is characterized by vulvar scarring, loss of the normal architecture, and whitish, crinkled vulvar skin. Dyspareunia can result from vulvar fissures, erosions, scarring, and introital narrowing associated with LS dermatologic changes [4]. Lichen planus (LP), another vulvar dystrophy, can, unlike LS, involve both the vulva and vagina. Due to changes in vulvar and vaginal integrity, dyspareunia also may result, although the prevalence with LP is lower as compared to LS. Lichen simplex chronicus, or squamous cell hyperplasia, is not as prevalent as LS or LP but when present usually occurs in the older age group. The diagnostic classification of menopause and related disorders developed by the North American Menopause Society is shown in Table 6.2 [5].

Table 6.2 Diagnostic classification of menopause and related disorders
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5 Vulvar Pain

Pain often accompanies vulvar infection, dermatoses, estrogen loss, and allergic/contact dermatitis etiologies. After eliminating recognizable causes of vulvar pain, the diagnosis of vulvodynia can be made, as this pain condition is a diagnosis of exclusion. Women with vulvodynia may complain of mild vulvar discomfort to searing vulvar pain. Clinicians must rule out specific infectious, inflammatory, neoplastic, or neurologic disorders before treating the woman for this condition.

6 Vulvodynia

In 2014, the International Society for the Study of Vulvovaginal Disease (ISSVD), the International Society for the Study of Women’s Sexual Health (ISSWSH), and the International Pelvic Pain Society (IPPS) revised the terminology of vulvar pain, on the basis of the significant increase in high-quality etiologic studies published in the last decade (Table 6.3) [6]. The table below describes those vulvar pain conditions, for which a cause can be clearly identified, and vulvodynia, where there is no clear identifiable cause.

Table 6.3 ISSVD terminology and classification of vulvar pain
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By the age of 40 years, 7–8% of women report vulvar pain consistent with vulvodynia [7]. Despite the high prevalence of this pain condition, the number of clinical trials testing the effectiveness of pharmacologic interventions is relatively sparse. Below are several that are in common use.

7 Tricyclic Antidepressant (TCA)

TCAs, both topical and oral formulations, are commonly used as first-line treatments for vulvodynia. Two RCTs and two case series have been published with oral treatment and one prospective and one retrospective study with topical therapy. Data suggest that TCAs alter nociceptive processing by prolonging synaptic activity of norepinephrine and serotonin, thereby enhancing descending inhibitory action in the spinal cord [8].

One double-blind placebo-controlled RCT compared (1) oral desipramine 25 mg with placebo cream, (2) lidocaine 5% cream and oral desipramine, (3) lidocaine 5% cream with placebo tablets, and (4) placebo cream and tablets in 133 women with localized provoked vulvodynia (LPV) [9]. Reduction of pain, the primary endpoint as measured by the tampon test, was similar for all treatment arms at 12 weeks: 24% for desipramine-placebo, 36% for lidocaine-desipramine, 33% for placebo-placebo, and 20% for lidocaine cream-placebo. Similarly, no differences were observed between the treatment arms in self-reported daily pain and intercourse pain.

The second RCT also found negative findings when low-dose amitriptyline, 10–20 mg amitriptyline plus topical steroid, and a self-management program (consisting of cognitive behavioral therapy (CBT), education, and physical and sex therapy) were compared in 53 women with provoked, unprovoked, or mixed vulvodynia with symptoms [10]. Therapy continued for 12 weeks and was evaluated on the basis of change from baseline for pain scores on the McGill Pain Questionnaire (MPQ). No significant difference was found in reduction of pain scores among the three groups, but significant within-group reduction in pain was seen in the self-management group only.

In contrast, Reed et al. presented a prospective case series of 209 women with mixed vulvodynia types (generalized and localized) receiving amitriptyline or desipramine (at a starting dose of 25 mg and titrated up weekly) and found the antidepressant-treated patients showed greater improvement than the control group [11]. Similarly, a retrospective case series by Munday et al. included 33 women with mixed vulvodynia types (generalized and localized) and reported that amitriptyline or desipramine resulted in a complete response in 47% of women [12]. However, in a retrospective case series conducted by McKay et al., there was no improvement in pain with 40–60 mg/day of amitriptyline in 20 women with generalized vulvodynia [12]. Pain measures were not identified in either the Munday et al. or the McKay et al. studies.

Pagano and Wong conducted a prospective study in 150 women with LPV using topical amitriptyline cream [13]. They found that 10% had excellent improvement, 29% had moderate improvement, 17% had slight improvement, and 44% had no response as measured by questionnaires. In a retrospective study, Nyirjesy et al. treated 38 women with LPV with a combination of 2% amitriptyline and 2% baclofen cream and reported that 53% were very much improved, 18% moderately improved, and 29% had little or no improvement in the frequency of intercourse, VAS scores, and on an interview survey [14].

TCAs are frequently used to treat vulvodynia, but controlled trials demonstrate limited efficacy. Moreover, side effects, such as drowsiness, constipation, nausea, dizziness, and sexual dysfunction, may occur. Although extremely rare, cardiac arrhythmias and conduction disturbances have been reported. Currently, TCAs are not recommended for vulvodynia treatment.

8 Anticonvulsants

Gabapentin, the most commonly used anticonvulsant to treat vulvodynia, acts by binding to alpha2delta-1 subunits of calcium channels in the central nervous system [15]. A retrospective case series by Boardman et al. examined topical gabapentin cream (2–6%) in a study that included 51 women with LPV and generalized vulvodynia [16]. In this study, 80% of subjects showed greater than 50% improvement using visual analogue scores.

Only two retrospective case series with oral gabapentin therapy have been conducted. Harris et al. reported that among 601 women with generalized unprovoked vulvodynia, 64% had adequate resolution, but a high percentage of subjects had comorbidities, and rating scales were not used [12]. Ben David found significant improvement of symptoms when rated on a visual analogue scale (VAS) in 73 women with vulvodynia (unspecified type). Although the quality of evidence is low, data suggests that gabapentin may be effective and can be offered to women with vulvodynia; however, it is unclear which subgroups may respond. Currently, a multicenter double-blind RCT is underway to determine its efficacy in the treatment of women with LPV [17]. These findings may provide data on its efficacy and safety in this group of women.

In addition to gabapentin, lamotrigine also has been investigated. By inhibiting voltage-sensitive sodium channels and the release of the excitatory amino acid glutamate, lamotrigine may suppress pathways involved in central neuronal hyperexcitability and persisting pain [15]. Although 1 open label study evaluated oral lamotrigine in 43 women with LPV and found significant reductions in the MPQ and VAS rating scales, there are not enough data to recommend routine use [12].

9 Antinociceptive Agents

Lidocaine exerts its analgesic effect via blockade of sodium channels on peripheral nociceptors and by blocking transmission of discharges from peripheral sensory nerves [18]. Sensitization of the peripheral vestibular nerves has been suggested as a possible mechanism of the pain in vestibulodynia. Therefore the theory behind the use of local anesthetics is to achieve long-lasting desensitization of the vestibular nerves.

The efficacy of topical lidocaine has been investigated in three trials and injectable lidocaine in five studies. The majority have shown little to no effect, with the exception of overnight use and concomitant corticosteroid therapy. Zolnoun reported that 54% of women had at least a 50% reduction in dyspareunia following overnight use of topical 5% lidocaine ointment in a case series of 69 subjects [19]. In contrast, Danielsson found no difference between topical 5% lidocaine ointment and electromyographic (EMG) feedback in 46 women with LPV in an RCT using a vulvar algesiometer or in quality of life or sexual functioning [20]. Similarly, Bohm-Starke compared EMG to topical lidocaine in a case-control study of 35 women with LPV and found no differences between treatments using pressure pain thresholds and questionnaires [12].

In a case series of 27 women with LPV, Rapkin et al. reported that 46% improved on the McGill Pain Questionnaire (MPQ), 57% by self-report, and 41% on algesiometer following administration of epidural, pudendal, and vulvar injections of ropivacaine and bupivacaine [21]. McDonald and Rapkin also reported in a case series a significant decrease in pain on the MPQ, but not intercourse pain, using the same anesthetics and methods of administration in 32 women with vulvodynia [22].

The efficacy of submucosal infiltrations of lidocaine combined with corticosteroids also has been investigated. In a prospective case series of 22 women with LPV, Murina et al. found 68% showed some improvement with a combination of lidocaine and methylprednisolone, and 32% had complete improvement [23]. Both Dede and Segal reported case studies where women with LPV had complete remission following lidocaine and betamethasone submucosal infiltrations [12].

Considering a 30% placebo rate in women with vulvodynia, the improvement reported with lidocaine alone or with combined therapy, regardless of route of administration, is modest. However, given the ease of topical administration, its low cost, and safety when used as directed, it provides a useful option for the treatment of this condition. In select patients, lidocaine injections are an alternative approach.

The rationale for the use of capsaicin in the treatment of vulvodynia is based on increased vanilloid receptor (VR1) innervation found in this disorder and the agonist effects of capsaicin on vanilloid receptors located in the peripheral terminals of nociceptors [24]. After hyperesthesia to the initial exposure, capsaicin produces a long-lasting desensitization to burning and pain.

One prospective and one retrospective case series have evaluated the efficacy of capsaicin cream in LPV. In the prospective study of 33 women receiving 0.05% capsaicin cream, 59% improved and 41% showed no improvement in dyspareunia [25]. Steinberg conducted a retrospective case series of 52 women with LPV and found that application of 0.025% capsaicin cream resulted in significant improvement on the touch test and Marinoff dyspareunia scale but provided no absolute numbers [12]. However, in both studies, lidocaine was given preceding the capsaicin to prevent irritation/burning on administration, so it is impossible to isolate the effect of capsaicin. Because of the potential for significant adverse events, such as serious application site burns, and limited data on efficacy, capsaicin is not recommended as a standard treatment for vulvodynia.

Botulinum (Botox®) (BTA) inhibits the release of glutamate and substance P from nociceptive neurons [26]. Current hypotheses suggest that the inhibition of these nociceptors may reduce peripheral and central sensitization associated with vulvodynia. The efficacy of BTA has been evaluated in one double-blind placebo-controlled RCT and three case series. The controlled study found no difference between BTA (100u) and placebo in level of pain on a VAS scale, quality of life, and sexual function in 64 women with LPV [27].

In contrast, a prospective case series of 20 women with LPV reported that 80% of women had an improvement in pain, and 72% were able to have sexual intercourse following 100 U of BTA [28]. Quality of life and sexual function also improved. In another prospective case series of 39 women with LPV, Bertolasi et al. reported that 63% recovered completely from vaginismus secondary to LPV, and 15% needed reinjections with BTA (a mean dose of 25 U was used per treatment session) [12]. However, in this study recovery was not defined. Similarly, lower doses (35–50 U) were found to significantly decrease pain using a VAS scale, decreased medication use, and improved quality of life in a retrospective study of 19 women with LPV [12].

Given that the RCT showed no improvement with BTA as compared to placebo, and because of the expense, complexity of the medical procedure, and potential for serious side effects, BTA is not recommended as first-line treatment for vulvodynia.

10 Anti-inflammatory Agents

Because tissue levels of interleukin (IL-β) have been reported to be significantly higher in the hymen region of the vestibule of women with LPV [29], corticosteroids also have been used to treat vulvodynia symptoms. As inhibitors of IL-1 production, corticosteroids should be a potential treatment option [30].

Three RCTS have been conducted evaluating the efficacy of topical corticosteroids in the treatment of vulvodynia. Munday compared a super high potency (clobetasol 0.05%) to a low potency (hydrocortisone 0.5%, “placebo”) corticosteroid in a crossover study of 22 women with LPV [31]. Seventy-three percent of women improved on clobetasol, while 60% improved with hydrocortisone cream. Desrochers et al. found significant improvement in pain and sexual function with both a 1% corticosteroid cream (type unreported) and cognitive behavioral therapy (CBT) in 111 women with LPV [32]. In a three-treatment arm study, Brown et al. found no difference between groups receiving amitriptyline vs. amitriptyline and 0.1% triamcinolone cream (medium potency) vs. self-management in 53 women with vulvodynia (mixed symptoms) [10]. These data suggest that topical corticosteroids are minimally effective in treating LPV. The lowest potency creams, such as hydrocortisone (1.0–2.5%), triamcinolone (0.025%), desonide (0.05%), or fluocinolone (0.01), can be prescribed for short 1- to 2-week intervals. It is unclear whether submucosal infiltrations of lidocaine combined with corticosteroids are effective, as no RCTs have been conducted to date.

Interferon (INF) is approved for the treatment of condylomata acuminate. It downregulates the expression of proinflammatory cytokines [33] and is theorized to be effective in LPV because tissue levels of cytokines have been reported to be significantly higher in the hymen region of the vestibule of LPV patients [29]. One RCT, three case series, and one case study have examined the efficacy of INF in LPV. Bornstein compared total perineoplasty to subtotal perineoplasty plus INF-α2b infiltration in 19 women with LPV and found that 67% of those undergoing total perineoplasty had a complete response compared to 70% of those having subtotal perineoplasty + INF-α [34]. In a prospective case series of 55 women, 49% of women treated with INF-α had substantial or partial improvement in coital pain and vestibular tenderness [35]. Of the 19 who elected to have surgery, 84% had a substantial improvement, and 11% had partial improvement in symptoms. Complete remission was reported in the majority of subjects in two small retrospective studies and one case study[12]. Further studies are necessary to determine if INF alone, or combined with surgery, is an effective treatment for LPV.

In a double-blind, placebo-controlled RCT of 34 women with LPV, Nyirjesy found that 54% of women receiving cromolyn cream, a mast cell stabilizer, compared to 38% of those receiving placebo cream had at least a 50% improvement in dyspareunia and vestibular tenderness [36]. In another double-blind, placebo-controlled RCT of 40 women with LPV, Donders found that fibroblast lysate cream, containing a variety of anti-inflammatory cytokines, produced a significant, although modest reduction in vestibular sensitivity and intercourse pain compared to placebo [37]. Another intervention, montelukast, reduces inflammation by inhibiting cysteinyl leukotriene receptors. A case-control study with montelukast was conducted in 47 women with LPV and found 52% were improved compared to 15% improvement with controls [38]. At this time, cromolyn cream, lysate cream, or montelukast is not recommended for use in the treatment of LPV.

11 Novel Agent

A double-blind study of enoxaparin, a low-molecular-weight heparin with anti-heparanase properties, was recently conducted in 40 women with LPV, based on findings of increased anti-heparanase in the vestibule of women with vulvodynia [39]. Compared to placebo, self-administration of enoxaparin (40 mg daily for 90 days) produced a significant, although modest, reduction in dyspareunia and vestibular sensitivity to a Q-tip exam. Decreased vestibular sensitivity was correlated with a reduction in intraepithelial-free nerve fibers in the enoxaparin group, but not in the placebo group, suggesting that enoxaparin may reduce neuroproliferation and penetration of nerve fibers in the epithelium.

12 Summary

Medical management of vulvar conditions depends on evidence-based guidance from various governmental agencies and professional societies. Those for vulvar infection, atrophy, and dystrophies are updated on a regular basis. However, for vulvodynia, there is a lack of significant efficacy in most pharmacologic interventions used. With vulvodynia, the patient, with her clinician, should decide if the risk profile is worth the limited efficacy of the treatment.

Medical Treatment: Breaking a Myth

  • Although tricyclic antidepressants are frequently used to treat vulvodynia, controlled trials demonstrated limited efficacy. Currently, they are not recommended for vulvodynia treatment