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New concepts in vulvodynia
New concepts in vulvodynia Libby Edwards, MD Charlotte, NC Vulvodynia is chronic vulvar burning/pain without clear medical findings. The etiology of vulvodynia is unknown and health care professionals should thoroughly rule out specific, treatable causes or factors such as dermatoses or group B Streptococcus infections. Vulvodynia is divided into 2 classes: vulvar vestibulitis syndrome is vestibule-restricted burning/pain and is elicited by touch; dysesthetic vulvodynia is burning/pain not limited to the vestibule and may occur without touch/pressure. After diagnosis, critical factors in successful patient management include education and psychological support/counseling. Unfortunately, clinical trials on potential vulvodynia therapies have been few. Standard therapy includes treating neuropathic pain (eg, tricyclic medications, gabapentin) thought to play a role. Additional therapies may be considered: pelvic floor rehabilitation combined with surface electromyography, interferon alfa, estrogen creams, and surgery. Importantly, any therapy should be accompanied by patient education and psychological support. Because definitive data on effective therapies are lacking, further clinical investigations of treatment options are warranted. (Am J Obstet Gynecol 2003;189:S24-S30.)
Key words: Vulvodynia, vulvar vestibulitis syndrome, dysesthetic vulvodynia
Vulvodynia is defined as chronic vulvar burning, stinging, rawness, soreness, or pain in the absence of objective clinical or laboratory findings to explain these symptoms. Itching is absent or is a minor symptom that does not produce a need to scratch. Although believed in the past to be uncommon, vulvodynia is now recognized as a fairly frequent syndrome. Data from a population-based study funded by the National Institutes of Health (NIH) found that 15.7% of women reported lower genital tract discomfort persisting 3 months or longer.1 Its frequency is underestimated partially because some physicians dismiss this problem as psychological and relatively unimportant. Also, affected women are reluctant to discuss their symptoms, which are perceived as unusual and possibly ‘‘all in the head.’’ As vulvodynia receives increased attention by both the medical profession and the media, more women are aggressively seeking care; thus, the increased frequency of vulvodynia is being realized. Recently, the term vulvar dysesthesia has been suggested as a more appropriate designation for vulvodynia, but this new terminology has not yet been universally adopted and will not be used in this article.
From the Southeast Vulvar Clinic. Received for publication January 30, 2003; revised March 11, 2003; accepted June 11, 2003. Reprint requests: Libby Edwards, MD, Southeast Vulvar Clinic, 401 S Sharon Amity Rd, Suite A, Charlotte, NC 28211. E-mail: ledwardsmd@ aol.com Ó 2003, Mosby, Inc. All rights reserved. 0002-9378/2003 $30.00 + 0 doi:10.1067/S0002-9378(03)00790-7
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Etiology The etiology of vulvodynia is unknown, and there may be multiple causes of this nonspecific syndrome. Initially, psychosexual dysfunction was commonly believed to be the cause of vulvodynia.2 Chronic subclinical yeast infection was also believed to play a role,3 but clinicians have found antifungal medications to be generally inadequate for patients with undocumented yeast infections. In the 1980s, subclinical human papillomavirus infection was reported as a frequent cause of vulvodynia, primarily because normal vulvar skin can often exhibit large, clear epidermal cells that mimic koilocytes on biopsy.4,5 The advent of sophisticated testing for human papillomavirus has demonstrated that this virus is absent in most women with vulvar pain.6,7 Recently, different causes have been implicated, including neuropathic pain, particularly complex regional pain syndrome (formerly called reflex sympathetic dystrophy), and pudendal neuralgia.8,9 The role of neuropathic pain in vulvodynia is supported by good response rates when patients are treated for neuropathic pain. Other possible causes of vulvodynia include an increase in cutaneous nerves and mast cells.10,11 Most clinicians believe that vulvodynia is not an inflammatory condition; however, there is evidence supporting the presence of increased inflammation in patients with vulvodynia.12,13 In addition, most women with vulvodynia exhibit pelvic floor abnormalities, which may serve as causative, permissive, or aggravating factors.14,15 Interestingly, the onset of vulvodynia in some women has been preceded by laser therapy, commonly used for genital wart or malignancy removal.16
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Scientists addressing pain at a recent vulvodynia workshop at the NIH (April 14 and 15, 2003) discussed other factors that may well be operative, including pain originating in the pudendal nerve, levator ani nerve, and pelvic nerves. Cross sensitization and cross-talk between 1 or more of these nerves and others may explain some aspects of regionalized pain. Abnormalities of sensation, with amplification of sensation by altered central sensitization and increased nerve fiber generation in the presence of injury were reported as well. Information showing a pain-susceptibility gene and gender factors also was introduced. Influences by inflammogenic products from a subgroup of fibroblasts were discussed, as was referred visceral pain perhaps playing a role in the discomfort of vulvodynia. Myofascial pain as a factor in women with trigger points was discussed. Data were presented showing that estrogen can both lower the pain threshold and also be a potent mediator of peripheral nerve remodeling. In addition, information regarding pharmacologic therapy to include the use of selective serotonin reuptake inhibitor was discussed, and capsaicin as a depleter of substance P was presented. Visceral K opioid and K agonists were discussed, and there were suggestions that combining analgesic therapies may be beneficial. In addition, the manifestation of vulvodynia may be caused by more than 1 factor and may vary in each patient.17 Although most clinicians find that depression and anxiety are common and appear to exacerbate vulvodynia, clinical studies do not support psychosexual dysfunction as a cause for vulvodynia, and patients do not have a higher-than-background incidence of childhood sexual or physical abuse.18,19 However, interstitial cystitis, headaches, fibromyalgia, and irritable bowel syndrome are overrepresented in women with vulvodynia, and depression is commonly present, worsening a patient’s symptoms.2 The clinical management of vulvodynia should begin with a careful examination to rule out skin disease and infection as causes of vulvar burning or pain (Table I). These conditions can sometimes be mistaken for vulvodynia, particularly when the abnormality is limited to the vagina. Diagnosis Before the diagnosis of vulvodynia can be made, specific causes of burning and irritation must be ruled out. Infection, particularly that caused by Candida albicans, is often the first working diagnosis. However, itching is the predominant symptom in C albicans infections, with secondary pain and rawness. Burning, soreness, rawness, and irritation are common with yeast infections caused by C glabrata, C parapsilosis, C krusei, and Saccharomyces cerevisiae. A vaginal fungal culture may be required because these organisms can be difficult to detect with only micropscopic analysis of vaginal secre-
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Table I. Evaluation of patients with vulvar pain Examination of vulva for abnormal redness, erosions, crusting, ulceration, hypopigmentation Cotton swab test to identify areas of pain on pressure (eg, vestibule) Sensory neurologic examination for allodynia and symmetrical sensation Examination for vaginal redness, erosions, pallor, dryness Biopsy of specific skin findings for evaluation by dermatopathologist Microscopic evaluation of vaginal secretions for yeast, pH, increased white blood cells Culture for Candida (exclusive of C albicans) and bacteria (especially group B Streptococcus) Evaluation for depression and impact on quality of life Classification of vulvar vestibulitis syndrome or dysesthetic vulvodynia
tions. In contrast to C albicans, most other yeast infections do not produce pseudohyphae or hyphae in the vagina, but only small, budding yeasts. Also, these types of yeast infections are often resistant to therapy, so a lack of improvement with antifungal therapy does not rule out a role for yeasts in vulvodynia. The identification of yeast does not ensure that the cause of symptoms has been identified, but women with chronic symptoms deserve treatment in case their symptoms are related. In addition to a fungal culture, a routine vaginal culture is indicated for any patient with unexplained, chronic vulvovaginal symptoms. Although nonpathogens that do not benefit from treatment are occasionally identified, an occasional patient exhibits a heavy growth of group B Streptococcus. Although group B Streptococcus (ie, S agalactiae) are usually asymptomatic colonizers in the vagina, many clinicians believe that they occasionally produce vulvar burning or irritation.20,21 Patients who test positive for group B Streptococcus may benefit from penicillin administration. Skin diseases of the vulva or vagina can also cause pain. Frequently mistaken for vulvodynia, lichen planus is a common cause of vulvar pain. Lichen planus manifests through vaginal erosions, resulting in an inflammatory vaginal discharge even in the absence of vulvar involvement. This causes an irritant contact dermatitis of the vulvar vestibule or vaginal introitus.22 Inflammatory vaginitis may occasionally be caused by other erosive skin diseases, such as cicatricial pemphigoid or pemphigus vulgaris.23 More common noninfectious causes of vaginal inflammation include atrophic vaginitis and a clinical syndrome seen in premenopausal women consisting of diffuse vaginal erythema and vaginal secretions that are microscopically purulent and exhibit an increase in immature epithelial cells. This syndrome has been termed desquamative inflammatory vaginitis by Sobel.24 If the vagina and vaginal secretions are not examined, these causes of vulvar burning may not be properly identified. Although lichen sclerosus and lichen simplex chronicus
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Table II. Nonspecific activities for managing vulvodynia Validate symptoms, be supportive Treat any objective abnormalities Discontinue irritants (eg, excessive washing, irritating lubricants, tight clothing, douching, nonessential medications, sanitary pads, hair dryers) Apply lubrication during sexual activity (eg, vegetable oil, Astroglide) Apply Xylocaine 2% jelly or 5% ointment for pain 20 min before sexual activity Apply cold compresses (eg, crushed ice) Address and manage depression Offer education (including written material) for both patient and partner Refer patient for membership in National Vulvodynia Association Refer both patient and partner for sex therapy and counseling to help cope with symptoms
(also called squamous hyperplasia, eczema, or neurodermatitis) can result in burning, rawness, or soreness, the patient typically reports significant itching with resulting pain on scratching, and secondary excoriations and erosions are present. When the vulvar skin, vagina, and vaginal smear appear normal and no infection or skin disease is present, the patient is diagnosed with vulvodynia. Often, a patient exhibits mild conditions that are unlikely to account for long-standing pain, such as a vulvovaginal Candida infection, mild erythema, or group B streptococcal infection. However, these abnormalities should be treated and, if necessary, suppressive therapy should be instituted to prevent recurrence. Those patients who remain symptomatic can be diagnosed as having vulvodynia, and the chief cause is believed to be neuropathic pain. There are 2 major pain patterns in women with vulvodynia—vulvar vestibulitis syndrome or dysesthetic vulvodynia—with considerable overlap in many patients.3 This distinction is important, however, because some therapies are useful only for women with vulvar vestibulitis syndrome. Vulvar vestibulitis syndrome is defined as burning or pain that is localized strictly to the vestibule of the vulva and is provoked by pressure or friction in the vestibule.25-27 Spontaneous pain is minimal or absent. Pain in vulvar vestibulitis syndrome is commonly associated with intercourse, tampon use, binding clothes, and bicycle riding, among others. There is usually, but not always, an abnormal degree of redness in the vestibule on physical examination. Touching the vulva with a cotton-tipped applicator produces pain only in the vestibule. Vulvar vestibulitis syndrome is observed primarily in premenopausal women. The second pattern of vulvodynia is dysesthetic vulvodynia, which is associated with burning or pain that is not limited to the vestibule and may occur without touch or pressure.3 Patients often experience pain on
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touch within the vestibule, but their pain is not limited to this area or they may experience spontaneous pain. Redness may be present. Treatment options Once vulvodynia has been properly diagnosed and the pain pattern identified, education for both the patient and, when possible, her partner is crucial in the management of vulvodynia. Furthermore, the patient’s symptoms should be validated as real. Many women are convinced that their symptoms result from a yeast infection or are fearful that their symptoms signify a serious underlying medical illness or future infertility. Patients need reassurance regarding these concerns and that their symptoms are not caused by a sexually transmitted disease (eg, human immunodeficiency virus) or life-threatening disease (eg, cancer). Vulvodynia is often devastating, affecting a patient’s personal relationships and quality of life. Depression is a common symptom and should be addressed.28 Most patients benefit from the newer-generation antidepressant medications, preferably combined with counseling. The clinician should make it clear that counseling and antidepressant therapy are recommended not to treat their pain, but because they can minimize the depression and disruption of personal relationships. A referral to couple counseling is ideal and can help the patient and her partner cope with vulvodynia. A therapist with expertise in sex therapy is preferred to help the couple to discover alternative types of painless sexual activity. Patient education is also important and is facilitated by patient brochures providing assurance that vulvodynia is a ‘‘real’’ disease. In addition, joining the National Vulvodynia Association (www.nva.org), a clearinghouse for information and updates on vulvar pain, helps both to inform patients and to alleviate the sense of isolation that many patients may experience. A variety of general nonspecific measures are available to increase the comfort level of women with vulvodynia (Table II). All potential irritants should be eliminated, including the frequent application of medications, particularly creams, that uniformly contain alcohols and other irritating substances.29 Excessive washing of the vulvar region by patients is common, and many commercial lubricants (eg, K-Y lubricating jelly [Ortho McNeil, Raritan, NJ]) may cause irritation. Astroglide (BioFilm, Vista, Calif.) and vegetable oil are good alternatives. In addition, Xylocaine (AstraZeneca, Wilmington, Del) 2% jelly (does not burn on application) and 5% ointment (brief burning sensation on application but is more potent) can help relieve the symptoms of burning in many women and, when applied liberally 20 minutes before sexual activity, may facilitate intercourse. Also, the application of cold compresses or ice to the vulva may help relieve symptoms.
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There are almost no scientific data on the efficacy of therapies for vulvodynia. Clinical trials are primarily limited to small, open series of patients, and placebocontrolled studies are too small to yield very useful data. However, because vulvodynia has gained recognition as a common, treatable entity, more studies are ongoing or planned. Specific first-line therapy for most patients with either form of vulvodynia is standard therapy for neuropathic pain (Table III). Tricyclic medications, particularly amitriptyline (Elavil, AstraZeneca) and desipramine (Norpramin, Aventis Pharmaceuticals, Bridgewater, NJ) improve pain substantially in most patients who can tolerate doses of 100 to 150 mg.30 Patients must be counseled that although these medications are known primarily for their antidepressant effects, they are also being used for their beneficial effects on neuropathic pain. Fortunately, many information sheets provided by pharmacies currently list these medications as commonly indicated for pain (although the pain indications are not approved by the US Food and Drug Administration). Patients who believe they are receiving the medication to treat depression are likely to feel deceived and therefore may not take their medication. With amitriptyline, patients should be started on a half of a 10-mg tablet and the dose should be gradually increased to minimize potential adverse reactions, until the total dose is 150 mg or symptoms are controlled, whichever occurs first. If unacceptable drowsiness or fatigue occurs, the dose can be decreased slightly and the patient given a week to acclimate before trying again to increase the dose. If the patient continues to experience drowsiness, desipramine, which is less sedating, can be substituted using the same dosing schedule (ie, target dose of 125 to 150 mg/day). However, desipramine is more likely to produce anxiety and tremulousness compared with amitriptyline, so, occasionally, patients might benefit from combination therapy with these 2 drugs to minimize these side effects while maintaining the beneficial effects. Other side effects of tricyclic medications include dryness of the mouth and eyes, constipation, increased appetite, and, rarely, urinary retention. For women who cannot tolerate adequate doses of tricyclic medications or who fail to improve, gabapentin (Neurontin, Parke-Davis, Morris Plains, NJ) may be considered. This medication is effective in diabetic neuropathy and postherpetic neuralgia at doses of 3600 mg/day or less.31,32 Anecdotally, many clinicians have reported beneficial effects of gabapentin in treating vulvodynia.33,34 Generally, this anticonvulsant is better tolerated and less sedating than tricyclic medications. However, it should be administered in divided doses 3 to 4 times a day, it is more expensive than amitriptyline, and it also has several side effects, including drowsiness, fatigue, dizziness, and ataxia. Similar to tricyclic medi-
Table III. Standard therapy for vulvodynia Vulvar vestibulitis syndrome
Dysesthetic vulvodynia
Treatment for neuropathy Tricyclic medications (# 150 mg/d) Gabapentin (# 3,600 mg/d)
Treatment for neuropathy Tricyclic medications (# 150 mg/d) Gabapentin (# 3,600 mg/d) Pelvic floor evaluation and rehabilitation
Pelvic floor evaluation and, if indicated, rehabilitation Intralesional INF-a Vestibulectomy
cations, this drug can be administered at low doses initially and gradually increased. In patients with either form of vulvodynia who cannot tolerate or do not respond to these medications, exercising pelvic floor muscles can be beneficial.35-37 Patients with vulvodynia are more likely than are asymptomatic women to exhibit increased resting pelvic floor muscle tension with fasciculation, but overall weakness.14 This profile probably predates symptoms and may predispose these women to the development of vulvodynia. These abnormalities are too subtle to identify during physical examination, but they can be identified by surface electromyography (Glazer method). This technique uses a small vaginal probe (about the size of a tampon) with electrical sensors connected to a computer. If pelvic floor abnormalities are identified by surface electromyography, then retraining the pelvic floor muscles with twice-daily exercises can be extraordinarily beneficial. A home training device can be attached to the vaginal probe so the patient can monitor the effectiveness of her exercise regimen as a biofeedback procedure. The exercises must be performed regularly, and improvement is generally observed after several months. After 8 to 12 months the exercises can be discontinued and patients generally retain the improvement in symptoms, although the profile of high-resting tension of pelvic floor muscles, fasciculation, and weakness usually returns. The abnormalities of the pelvic floor muscles also can be addressed through physical therapy. Physical therapy has the advantage of treating the associated abnormalities that may worsen the symptoms of vulvodynia. For example, vulvar pain syndromes are often associated with irritable bowel syndrome, fibromyalgia, and joint pain. An evaluation by a physical therapist may identify and help alleviate dysfunctional aspects of the musculoskeletal system, such as the obturator internus and coccygeus muscles, and the sacrospinous and sacrotuberous ligaments.38 Other areas that can be targeted by physical therapy include fascial attachment and tissue tension levels of the bladder and urethra, uterine mobility, and sacrococcygeal mobility and positioning.38 A recent retrospective study reported the response rate of 24
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Table IV. Additional anecdotal therapies for vulvodynia Triamcinolone trigger point injections Low-oxalate diet with calcium citrate supplementation Topical estrogen Topical capsaicin Antidepressant therapy (selective serotonin reuptake inhibitors) Topical lidocaine every 6 hours on a regular basis Acupuncture
patients with either vulvar vestibulitis syndrome or dysesthetic vulvodynia who were treated with pelvic floor rehabilitation by the Glazer method and concomitant physical therapy.38 Pain associated with sexual intercourse and daily activities decreased significantly, with pain levels decreasing by approximately 40% to 60%.38 Unfortunately, this type of training in physical therapy programs is not standard and the Glazer method of pelvic floor rehabilitation is not widely available. Additional therapies are available that can be administered to patients with vulvar vestibulitis syndrome. Interferon alfa (IFN-a) has been reported to be beneficial, primarily when injected locally.39,40 The most common regimen consists of IFN-a 1 million units injected 3 times per week for 4 weeks circumferentially at the periphery of the vestibule. In this procedure, the vestibule is divided into 12 areas as in a clock face; for example, a first injection could be given at the 6:00 position, the second injection at the 7:00 position, and so on until the entire periphery has been injected once. Patients may experience flu-like symptoms such as fever, malaise, and myalgias; pretreatment with acetaminophen or ibuprofen may minimize these symptoms. In addition, patients may experience significant injection-site pain, and pretreatment for 20 to 30 minutes with a topical anesthetic may help relieve the pain. Improvement 1 year after IFN-a therapy is variable.39,40 Another treatment option for patients with vulvar vestibulitis syndrome is surgical excision of the vestibule.36,41-43 The affected area is mapped and excised. Many surgeons remove all areas of the vestibule, including areas that do not exhibit pain, because vestibulectomy failures result in recurrences in remaining vestibule tissue. About 85% of patients experience a cure or remarkable improvement in their symptoms after surgery.41 However, dehiscence, recurrence of symptoms, or worsening of pain occasionally occurs after vestibulectomy. Although vestibulectomy was once the treatment of choice for vulvar vestibulitis syndrome, the scarcity of experienced surgeons, the discomfort of the procedure, the cost, and the success of less aggressive therapies have relegated this procedure to second- or third-line therapy. Other therapies have also been administered and may be considered for unresponsive patients (Table IV). For example, a patient occasionally reports pain that is very
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localized in origin. When 1 of these trigger points is identified, 0.2 to 0.3 mL of 3 mg/mL triamcinolone acetonide injected into the affected area may substantially improve pain within 1 to 2 weeks. An additional injection 4 to 6 months later occasionally resolves the pain permanently. In addition, the theory that high urinary and tissue oxalate levels cause pain in some patients has led to the use of a low-oxalate diet and mealtime calcium citrate supplementation to inhibit absorption of oxalate and reduce pain symptoms.44 Other studies have indicated that patients with vulvodynia do not have increased oxalate levels, and there is no correlation between oxalate levels and symptom improvement.45 Some clinicians anecdotally describe improvement in premenopausal and nonestrogen-deficient women by avoidance of all painful stimuli, including intercourse, for 1 to 2 months, along with the application of estrogen creams to the affected area. One unpublished clinical trial reported good results with the use of topical capsaicin, an over-the-counter agent used to treat postherpetic neuralgia. Care should be taken with the application of capsaicin because of its potential as a strong irritant. The newer selective serotonin reuptake inhibitor (SSRI) antidepressants show a limited effect on neuropathic pain, but, because depression is commonly associated with vulvodynia, improvement in pain may accompany an improvement in depression. In addition, there are theoretical reasons that some of the newer SSRIs may directly influence neuropathic pain. Most of the SSRIs can be given concomitantly with tricyclic medications, although most SSRIs can theoretically inhibit the metabolism of tricyclics. This clinician has not documented this serologically. Still, monitoring tricyclic levels in these patients is prudent. Ongoing suppressive antifungal therapy has been reported to be useful in some patients, primarily those who tend to develop monthly flares.46 In my experience, flaring before menses in both forms of vulvodynia is very common, but ongoing antifungal therapy is only minimally effective in patients who do not exhibit yeast on culture. The use of ‘‘antiyeast’’ diets low in yeast and sugars, yogurt administered either by mouth or as a douche, and Lactobacillus capsules either ingested by mouth or inserted in the vagina does not improve vulvodynia. A regular application of lidocaine has been suggested as a means of breaking the pain cycle. The topical immune response modifier imiquimod (Aldara, 3M Pharmaceuticals) has been suggested as a potential therapy because of its stimulation of the cellular immune system and induction of cytokines such as IFN-a. However, this medication is a potential irritant and no clinical studies on its use in vulvodynia have been published. Topical and oral corticosteroids are not useful for vulvar pain, except in the case of accompanying inflammatory skin disease such as lichen planus.
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Other unconventional therapies have been administered to treat vulvodynia. Botulinum toxin has been suggested as a therapy, and at least 1 open-label trial is ongoing. Acupuncture has also been found modestly useful.47,48 Early reports of some forms of laser ablation described improvement in vulvodynia.49 However, worsening pain and recurrence are common,15 and laser treatment is now contraindicated in women with vulvar pain. Similarly, other ablative therapies such as cryotherapy, trichloroacetic or bichloracetic acid, and electrocautery should be avoided because of the potential for increased burning and pain. Conclusions Vulvodynia is an important syndrome that has been largely dismissed until recently. In addition to treating the symptoms, the importance of psychological support and the treatment of depression should not be underestimated. Symptomatic improvement of vulvodynia with current therapies is slow, and inattention to patient education and depression often results in patients who do not take prescribed medication, who give up too quickly, and who suffer psychological repercussions of these symptoms more severely than necessary. A critical factor in the management of vulvodynia by health care professionals is to show compassion for the patient, to not dismiss pain symptoms, and to reinforce the idea that patients should not blame themselves.
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37. McKay E, Kaufman RH, Doctor U, Berkova Z, Glazer H, Redko V. Treating vulvar vestibulitis with electromyographic biofeedback of pelvic floor musculature. J Reprod Med 2001;46:337-42. 38. Hartmann EH, Nelson C. The perceived effectiveness of physical therapy treatment on women complaining of chronic vulvar pain and diagnosed with either vulvar vestibulitis syndrome or dysesthetic vulvodynia. Journal of the Section on Women’s Health 2001;25:13-8. 39. Horowitz BJ. Interferon therapy for condylomatous vulvitis. Obstet Gynecol 1989;73:446-8. 40. Marinoff SC, Turner ML, Hirsch RP, Richard G. Intralesional alpha interferon: cost-effective therapy for vulvar vestibulitis syndrome. J Reprod Med 1993;38:19-24. 41. McCormack WM, Spence MR. Evaluation of the surgical treatment of vulvar vestibulitis. Eur J Obstet Gynecol Reprod Biol 1999;86:135-8. 42. Schneider D, Yaron M, Bukovsky I, Soffer Y, Halperin R. Outcome of surgical treatment for superficial dyspareunia from vulvar vestibulitis. J Reprod Med 2001;46:227-31.
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43. Bornstein J, Zarfati D, Goldik Z, Abramovici H. Vulvar vestibulitis: physical or psychosexual problem? Obstet Gynecol 1999;93:876-80. 44. Solomons CC, Melmed MH, Heitler SM. Calcium citrate for vulvar vestibulitis: a case report. J Reprod Med 1991;36:879-82. 45. Baggish MS, Sze EH, Johnson R. Urinary oxalate excretion and its role in vulvar pain syndrome. Am J Obstet Gynecol 1997;177: 507-11. 46. Metts JF. Vulvodynia and vulvar vestibulitis: challenges in diagnosis and management. Am Fam Physician 1999;59:1547-56, 1561-2. 47. Danielsson I, Sjoberg I, Ostman C. Acupuncture for the treatment of vulvar vestibulitis: a pilot study. Acta Obstet Gynecol Scand 2001;80:437-41. 48. Powell J, Wojnarowska F. Acupuncture for vulvodynia. J R Soc Med 1999;92:579-81. 49. Reid R, Omoto KH, Precop SL, Berman NR, Rutledge LH, Dean SM, et al. Flashlamp-excited dye laser therapy of idiopathic vulvodynia is safe and efficacious. Am J Obstet Gynecol 1995;172:1684-96; discussion 1696-701.
Key words: Vulvodynia, vulvar vestibulitis syndrome, dysesthetic vulvodynia
Vulvodynia is defined as chronic vulvar burning, stinging, rawness, soreness, or pain in the absence of objective clinical or laboratory findings to explain these symptoms. Itching is absent or is a minor symptom that does not produce a need to scratch. Although believed in the past to be uncommon, vulvodynia is now recognized as a fairly frequent syndrome. Data from a population-based study funded by the National Institutes of Health (NIH) found that 15.7% of women reported lower genital tract discomfort persisting 3 months or longer.1 Its frequency is underestimated partially because some physicians dismiss this problem as psychological and relatively unimportant. Also, affected women are reluctant to discuss their symptoms, which are perceived as unusual and possibly ‘‘all in the head.’’ As vulvodynia receives increased attention by both the medical profession and the media, more women are aggressively seeking care; thus, the increased frequency of vulvodynia is being realized. Recently, the term vulvar dysesthesia has been suggested as a more appropriate designation for vulvodynia, but this new terminology has not yet been universally adopted and will not be used in this article.
From the Southeast Vulvar Clinic. Received for publication January 30, 2003; revised March 11, 2003; accepted June 11, 2003. Reprint requests: Libby Edwards, MD, Southeast Vulvar Clinic, 401 S Sharon Amity Rd, Suite A, Charlotte, NC 28211. E-mail: ledwardsmd@ aol.com Ó 2003, Mosby, Inc. All rights reserved. 0002-9378/2003 $30.00 + 0 doi:10.1067/S0002-9378(03)00790-7
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Etiology The etiology of vulvodynia is unknown, and there may be multiple causes of this nonspecific syndrome. Initially, psychosexual dysfunction was commonly believed to be the cause of vulvodynia.2 Chronic subclinical yeast infection was also believed to play a role,3 but clinicians have found antifungal medications to be generally inadequate for patients with undocumented yeast infections. In the 1980s, subclinical human papillomavirus infection was reported as a frequent cause of vulvodynia, primarily because normal vulvar skin can often exhibit large, clear epidermal cells that mimic koilocytes on biopsy.4,5 The advent of sophisticated testing for human papillomavirus has demonstrated that this virus is absent in most women with vulvar pain.6,7 Recently, different causes have been implicated, including neuropathic pain, particularly complex regional pain syndrome (formerly called reflex sympathetic dystrophy), and pudendal neuralgia.8,9 The role of neuropathic pain in vulvodynia is supported by good response rates when patients are treated for neuropathic pain. Other possible causes of vulvodynia include an increase in cutaneous nerves and mast cells.10,11 Most clinicians believe that vulvodynia is not an inflammatory condition; however, there is evidence supporting the presence of increased inflammation in patients with vulvodynia.12,13 In addition, most women with vulvodynia exhibit pelvic floor abnormalities, which may serve as causative, permissive, or aggravating factors.14,15 Interestingly, the onset of vulvodynia in some women has been preceded by laser therapy, commonly used for genital wart or malignancy removal.16
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Scientists addressing pain at a recent vulvodynia workshop at the NIH (April 14 and 15, 2003) discussed other factors that may well be operative, including pain originating in the pudendal nerve, levator ani nerve, and pelvic nerves. Cross sensitization and cross-talk between 1 or more of these nerves and others may explain some aspects of regionalized pain. Abnormalities of sensation, with amplification of sensation by altered central sensitization and increased nerve fiber generation in the presence of injury were reported as well. Information showing a pain-susceptibility gene and gender factors also was introduced. Influences by inflammogenic products from a subgroup of fibroblasts were discussed, as was referred visceral pain perhaps playing a role in the discomfort of vulvodynia. Myofascial pain as a factor in women with trigger points was discussed. Data were presented showing that estrogen can both lower the pain threshold and also be a potent mediator of peripheral nerve remodeling. In addition, information regarding pharmacologic therapy to include the use of selective serotonin reuptake inhibitor was discussed, and capsaicin as a depleter of substance P was presented. Visceral K opioid and K agonists were discussed, and there were suggestions that combining analgesic therapies may be beneficial. In addition, the manifestation of vulvodynia may be caused by more than 1 factor and may vary in each patient.17 Although most clinicians find that depression and anxiety are common and appear to exacerbate vulvodynia, clinical studies do not support psychosexual dysfunction as a cause for vulvodynia, and patients do not have a higher-than-background incidence of childhood sexual or physical abuse.18,19 However, interstitial cystitis, headaches, fibromyalgia, and irritable bowel syndrome are overrepresented in women with vulvodynia, and depression is commonly present, worsening a patient’s symptoms.2 The clinical management of vulvodynia should begin with a careful examination to rule out skin disease and infection as causes of vulvar burning or pain (Table I). These conditions can sometimes be mistaken for vulvodynia, particularly when the abnormality is limited to the vagina. Diagnosis Before the diagnosis of vulvodynia can be made, specific causes of burning and irritation must be ruled out. Infection, particularly that caused by Candida albicans, is often the first working diagnosis. However, itching is the predominant symptom in C albicans infections, with secondary pain and rawness. Burning, soreness, rawness, and irritation are common with yeast infections caused by C glabrata, C parapsilosis, C krusei, and Saccharomyces cerevisiae. A vaginal fungal culture may be required because these organisms can be difficult to detect with only micropscopic analysis of vaginal secre-
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Table I. Evaluation of patients with vulvar pain Examination of vulva for abnormal redness, erosions, crusting, ulceration, hypopigmentation Cotton swab test to identify areas of pain on pressure (eg, vestibule) Sensory neurologic examination for allodynia and symmetrical sensation Examination for vaginal redness, erosions, pallor, dryness Biopsy of specific skin findings for evaluation by dermatopathologist Microscopic evaluation of vaginal secretions for yeast, pH, increased white blood cells Culture for Candida (exclusive of C albicans) and bacteria (especially group B Streptococcus) Evaluation for depression and impact on quality of life Classification of vulvar vestibulitis syndrome or dysesthetic vulvodynia
tions. In contrast to C albicans, most other yeast infections do not produce pseudohyphae or hyphae in the vagina, but only small, budding yeasts. Also, these types of yeast infections are often resistant to therapy, so a lack of improvement with antifungal therapy does not rule out a role for yeasts in vulvodynia. The identification of yeast does not ensure that the cause of symptoms has been identified, but women with chronic symptoms deserve treatment in case their symptoms are related. In addition to a fungal culture, a routine vaginal culture is indicated for any patient with unexplained, chronic vulvovaginal symptoms. Although nonpathogens that do not benefit from treatment are occasionally identified, an occasional patient exhibits a heavy growth of group B Streptococcus. Although group B Streptococcus (ie, S agalactiae) are usually asymptomatic colonizers in the vagina, many clinicians believe that they occasionally produce vulvar burning or irritation.20,21 Patients who test positive for group B Streptococcus may benefit from penicillin administration. Skin diseases of the vulva or vagina can also cause pain. Frequently mistaken for vulvodynia, lichen planus is a common cause of vulvar pain. Lichen planus manifests through vaginal erosions, resulting in an inflammatory vaginal discharge even in the absence of vulvar involvement. This causes an irritant contact dermatitis of the vulvar vestibule or vaginal introitus.22 Inflammatory vaginitis may occasionally be caused by other erosive skin diseases, such as cicatricial pemphigoid or pemphigus vulgaris.23 More common noninfectious causes of vaginal inflammation include atrophic vaginitis and a clinical syndrome seen in premenopausal women consisting of diffuse vaginal erythema and vaginal secretions that are microscopically purulent and exhibit an increase in immature epithelial cells. This syndrome has been termed desquamative inflammatory vaginitis by Sobel.24 If the vagina and vaginal secretions are not examined, these causes of vulvar burning may not be properly identified. Although lichen sclerosus and lichen simplex chronicus
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Table II. Nonspecific activities for managing vulvodynia Validate symptoms, be supportive Treat any objective abnormalities Discontinue irritants (eg, excessive washing, irritating lubricants, tight clothing, douching, nonessential medications, sanitary pads, hair dryers) Apply lubrication during sexual activity (eg, vegetable oil, Astroglide) Apply Xylocaine 2% jelly or 5% ointment for pain 20 min before sexual activity Apply cold compresses (eg, crushed ice) Address and manage depression Offer education (including written material) for both patient and partner Refer patient for membership in National Vulvodynia Association Refer both patient and partner for sex therapy and counseling to help cope with symptoms
(also called squamous hyperplasia, eczema, or neurodermatitis) can result in burning, rawness, or soreness, the patient typically reports significant itching with resulting pain on scratching, and secondary excoriations and erosions are present. When the vulvar skin, vagina, and vaginal smear appear normal and no infection or skin disease is present, the patient is diagnosed with vulvodynia. Often, a patient exhibits mild conditions that are unlikely to account for long-standing pain, such as a vulvovaginal Candida infection, mild erythema, or group B streptococcal infection. However, these abnormalities should be treated and, if necessary, suppressive therapy should be instituted to prevent recurrence. Those patients who remain symptomatic can be diagnosed as having vulvodynia, and the chief cause is believed to be neuropathic pain. There are 2 major pain patterns in women with vulvodynia—vulvar vestibulitis syndrome or dysesthetic vulvodynia—with considerable overlap in many patients.3 This distinction is important, however, because some therapies are useful only for women with vulvar vestibulitis syndrome. Vulvar vestibulitis syndrome is defined as burning or pain that is localized strictly to the vestibule of the vulva and is provoked by pressure or friction in the vestibule.25-27 Spontaneous pain is minimal or absent. Pain in vulvar vestibulitis syndrome is commonly associated with intercourse, tampon use, binding clothes, and bicycle riding, among others. There is usually, but not always, an abnormal degree of redness in the vestibule on physical examination. Touching the vulva with a cotton-tipped applicator produces pain only in the vestibule. Vulvar vestibulitis syndrome is observed primarily in premenopausal women. The second pattern of vulvodynia is dysesthetic vulvodynia, which is associated with burning or pain that is not limited to the vestibule and may occur without touch or pressure.3 Patients often experience pain on
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touch within the vestibule, but their pain is not limited to this area or they may experience spontaneous pain. Redness may be present. Treatment options Once vulvodynia has been properly diagnosed and the pain pattern identified, education for both the patient and, when possible, her partner is crucial in the management of vulvodynia. Furthermore, the patient’s symptoms should be validated as real. Many women are convinced that their symptoms result from a yeast infection or are fearful that their symptoms signify a serious underlying medical illness or future infertility. Patients need reassurance regarding these concerns and that their symptoms are not caused by a sexually transmitted disease (eg, human immunodeficiency virus) or life-threatening disease (eg, cancer). Vulvodynia is often devastating, affecting a patient’s personal relationships and quality of life. Depression is a common symptom and should be addressed.28 Most patients benefit from the newer-generation antidepressant medications, preferably combined with counseling. The clinician should make it clear that counseling and antidepressant therapy are recommended not to treat their pain, but because they can minimize the depression and disruption of personal relationships. A referral to couple counseling is ideal and can help the patient and her partner cope with vulvodynia. A therapist with expertise in sex therapy is preferred to help the couple to discover alternative types of painless sexual activity. Patient education is also important and is facilitated by patient brochures providing assurance that vulvodynia is a ‘‘real’’ disease. In addition, joining the National Vulvodynia Association (www.nva.org), a clearinghouse for information and updates on vulvar pain, helps both to inform patients and to alleviate the sense of isolation that many patients may experience. A variety of general nonspecific measures are available to increase the comfort level of women with vulvodynia (Table II). All potential irritants should be eliminated, including the frequent application of medications, particularly creams, that uniformly contain alcohols and other irritating substances.29 Excessive washing of the vulvar region by patients is common, and many commercial lubricants (eg, K-Y lubricating jelly [Ortho McNeil, Raritan, NJ]) may cause irritation. Astroglide (BioFilm, Vista, Calif.) and vegetable oil are good alternatives. In addition, Xylocaine (AstraZeneca, Wilmington, Del) 2% jelly (does not burn on application) and 5% ointment (brief burning sensation on application but is more potent) can help relieve the symptoms of burning in many women and, when applied liberally 20 minutes before sexual activity, may facilitate intercourse. Also, the application of cold compresses or ice to the vulva may help relieve symptoms.
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There are almost no scientific data on the efficacy of therapies for vulvodynia. Clinical trials are primarily limited to small, open series of patients, and placebocontrolled studies are too small to yield very useful data. However, because vulvodynia has gained recognition as a common, treatable entity, more studies are ongoing or planned. Specific first-line therapy for most patients with either form of vulvodynia is standard therapy for neuropathic pain (Table III). Tricyclic medications, particularly amitriptyline (Elavil, AstraZeneca) and desipramine (Norpramin, Aventis Pharmaceuticals, Bridgewater, NJ) improve pain substantially in most patients who can tolerate doses of 100 to 150 mg.30 Patients must be counseled that although these medications are known primarily for their antidepressant effects, they are also being used for their beneficial effects on neuropathic pain. Fortunately, many information sheets provided by pharmacies currently list these medications as commonly indicated for pain (although the pain indications are not approved by the US Food and Drug Administration). Patients who believe they are receiving the medication to treat depression are likely to feel deceived and therefore may not take their medication. With amitriptyline, patients should be started on a half of a 10-mg tablet and the dose should be gradually increased to minimize potential adverse reactions, until the total dose is 150 mg or symptoms are controlled, whichever occurs first. If unacceptable drowsiness or fatigue occurs, the dose can be decreased slightly and the patient given a week to acclimate before trying again to increase the dose. If the patient continues to experience drowsiness, desipramine, which is less sedating, can be substituted using the same dosing schedule (ie, target dose of 125 to 150 mg/day). However, desipramine is more likely to produce anxiety and tremulousness compared with amitriptyline, so, occasionally, patients might benefit from combination therapy with these 2 drugs to minimize these side effects while maintaining the beneficial effects. Other side effects of tricyclic medications include dryness of the mouth and eyes, constipation, increased appetite, and, rarely, urinary retention. For women who cannot tolerate adequate doses of tricyclic medications or who fail to improve, gabapentin (Neurontin, Parke-Davis, Morris Plains, NJ) may be considered. This medication is effective in diabetic neuropathy and postherpetic neuralgia at doses of 3600 mg/day or less.31,32 Anecdotally, many clinicians have reported beneficial effects of gabapentin in treating vulvodynia.33,34 Generally, this anticonvulsant is better tolerated and less sedating than tricyclic medications. However, it should be administered in divided doses 3 to 4 times a day, it is more expensive than amitriptyline, and it also has several side effects, including drowsiness, fatigue, dizziness, and ataxia. Similar to tricyclic medi-
Table III. Standard therapy for vulvodynia Vulvar vestibulitis syndrome
Dysesthetic vulvodynia
Treatment for neuropathy Tricyclic medications (# 150 mg/d) Gabapentin (# 3,600 mg/d)
Treatment for neuropathy Tricyclic medications (# 150 mg/d) Gabapentin (# 3,600 mg/d) Pelvic floor evaluation and rehabilitation
Pelvic floor evaluation and, if indicated, rehabilitation Intralesional INF-a Vestibulectomy
cations, this drug can be administered at low doses initially and gradually increased. In patients with either form of vulvodynia who cannot tolerate or do not respond to these medications, exercising pelvic floor muscles can be beneficial.35-37 Patients with vulvodynia are more likely than are asymptomatic women to exhibit increased resting pelvic floor muscle tension with fasciculation, but overall weakness.14 This profile probably predates symptoms and may predispose these women to the development of vulvodynia. These abnormalities are too subtle to identify during physical examination, but they can be identified by surface electromyography (Glazer method). This technique uses a small vaginal probe (about the size of a tampon) with electrical sensors connected to a computer. If pelvic floor abnormalities are identified by surface electromyography, then retraining the pelvic floor muscles with twice-daily exercises can be extraordinarily beneficial. A home training device can be attached to the vaginal probe so the patient can monitor the effectiveness of her exercise regimen as a biofeedback procedure. The exercises must be performed regularly, and improvement is generally observed after several months. After 8 to 12 months the exercises can be discontinued and patients generally retain the improvement in symptoms, although the profile of high-resting tension of pelvic floor muscles, fasciculation, and weakness usually returns. The abnormalities of the pelvic floor muscles also can be addressed through physical therapy. Physical therapy has the advantage of treating the associated abnormalities that may worsen the symptoms of vulvodynia. For example, vulvar pain syndromes are often associated with irritable bowel syndrome, fibromyalgia, and joint pain. An evaluation by a physical therapist may identify and help alleviate dysfunctional aspects of the musculoskeletal system, such as the obturator internus and coccygeus muscles, and the sacrospinous and sacrotuberous ligaments.38 Other areas that can be targeted by physical therapy include fascial attachment and tissue tension levels of the bladder and urethra, uterine mobility, and sacrococcygeal mobility and positioning.38 A recent retrospective study reported the response rate of 24
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Table IV. Additional anecdotal therapies for vulvodynia Triamcinolone trigger point injections Low-oxalate diet with calcium citrate supplementation Topical estrogen Topical capsaicin Antidepressant therapy (selective serotonin reuptake inhibitors) Topical lidocaine every 6 hours on a regular basis Acupuncture
patients with either vulvar vestibulitis syndrome or dysesthetic vulvodynia who were treated with pelvic floor rehabilitation by the Glazer method and concomitant physical therapy.38 Pain associated with sexual intercourse and daily activities decreased significantly, with pain levels decreasing by approximately 40% to 60%.38 Unfortunately, this type of training in physical therapy programs is not standard and the Glazer method of pelvic floor rehabilitation is not widely available. Additional therapies are available that can be administered to patients with vulvar vestibulitis syndrome. Interferon alfa (IFN-a) has been reported to be beneficial, primarily when injected locally.39,40 The most common regimen consists of IFN-a 1 million units injected 3 times per week for 4 weeks circumferentially at the periphery of the vestibule. In this procedure, the vestibule is divided into 12 areas as in a clock face; for example, a first injection could be given at the 6:00 position, the second injection at the 7:00 position, and so on until the entire periphery has been injected once. Patients may experience flu-like symptoms such as fever, malaise, and myalgias; pretreatment with acetaminophen or ibuprofen may minimize these symptoms. In addition, patients may experience significant injection-site pain, and pretreatment for 20 to 30 minutes with a topical anesthetic may help relieve the pain. Improvement 1 year after IFN-a therapy is variable.39,40 Another treatment option for patients with vulvar vestibulitis syndrome is surgical excision of the vestibule.36,41-43 The affected area is mapped and excised. Many surgeons remove all areas of the vestibule, including areas that do not exhibit pain, because vestibulectomy failures result in recurrences in remaining vestibule tissue. About 85% of patients experience a cure or remarkable improvement in their symptoms after surgery.41 However, dehiscence, recurrence of symptoms, or worsening of pain occasionally occurs after vestibulectomy. Although vestibulectomy was once the treatment of choice for vulvar vestibulitis syndrome, the scarcity of experienced surgeons, the discomfort of the procedure, the cost, and the success of less aggressive therapies have relegated this procedure to second- or third-line therapy. Other therapies have also been administered and may be considered for unresponsive patients (Table IV). For example, a patient occasionally reports pain that is very
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localized in origin. When 1 of these trigger points is identified, 0.2 to 0.3 mL of 3 mg/mL triamcinolone acetonide injected into the affected area may substantially improve pain within 1 to 2 weeks. An additional injection 4 to 6 months later occasionally resolves the pain permanently. In addition, the theory that high urinary and tissue oxalate levels cause pain in some patients has led to the use of a low-oxalate diet and mealtime calcium citrate supplementation to inhibit absorption of oxalate and reduce pain symptoms.44 Other studies have indicated that patients with vulvodynia do not have increased oxalate levels, and there is no correlation between oxalate levels and symptom improvement.45 Some clinicians anecdotally describe improvement in premenopausal and nonestrogen-deficient women by avoidance of all painful stimuli, including intercourse, for 1 to 2 months, along with the application of estrogen creams to the affected area. One unpublished clinical trial reported good results with the use of topical capsaicin, an over-the-counter agent used to treat postherpetic neuralgia. Care should be taken with the application of capsaicin because of its potential as a strong irritant. The newer selective serotonin reuptake inhibitor (SSRI) antidepressants show a limited effect on neuropathic pain, but, because depression is commonly associated with vulvodynia, improvement in pain may accompany an improvement in depression. In addition, there are theoretical reasons that some of the newer SSRIs may directly influence neuropathic pain. Most of the SSRIs can be given concomitantly with tricyclic medications, although most SSRIs can theoretically inhibit the metabolism of tricyclics. This clinician has not documented this serologically. Still, monitoring tricyclic levels in these patients is prudent. Ongoing suppressive antifungal therapy has been reported to be useful in some patients, primarily those who tend to develop monthly flares.46 In my experience, flaring before menses in both forms of vulvodynia is very common, but ongoing antifungal therapy is only minimally effective in patients who do not exhibit yeast on culture. The use of ‘‘antiyeast’’ diets low in yeast and sugars, yogurt administered either by mouth or as a douche, and Lactobacillus capsules either ingested by mouth or inserted in the vagina does not improve vulvodynia. A regular application of lidocaine has been suggested as a means of breaking the pain cycle. The topical immune response modifier imiquimod (Aldara, 3M Pharmaceuticals) has been suggested as a potential therapy because of its stimulation of the cellular immune system and induction of cytokines such as IFN-a. However, this medication is a potential irritant and no clinical studies on its use in vulvodynia have been published. Topical and oral corticosteroids are not useful for vulvar pain, except in the case of accompanying inflammatory skin disease such as lichen planus.
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Other unconventional therapies have been administered to treat vulvodynia. Botulinum toxin has been suggested as a therapy, and at least 1 open-label trial is ongoing. Acupuncture has also been found modestly useful.47,48 Early reports of some forms of laser ablation described improvement in vulvodynia.49 However, worsening pain and recurrence are common,15 and laser treatment is now contraindicated in women with vulvar pain. Similarly, other ablative therapies such as cryotherapy, trichloroacetic or bichloracetic acid, and electrocautery should be avoided because of the potential for increased burning and pain. Conclusions Vulvodynia is an important syndrome that has been largely dismissed until recently. In addition to treating the symptoms, the importance of psychological support and the treatment of depression should not be underestimated. Symptomatic improvement of vulvodynia with current therapies is slow, and inattention to patient education and depression often results in patients who do not take prescribed medication, who give up too quickly, and who suffer psychological repercussions of these symptoms more severely than necessary. A critical factor in the management of vulvodynia by health care professionals is to show compassion for the patient, to not dismiss pain symptoms, and to reinforce the idea that patients should not blame themselves.
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