INTRODUCTION

Since the 1980’s, stunning  advances in research on vulvodynia have fostered better understanding of pain, as well as the intricacies of vulvovaginal anatomy and physiology. The result :a gradual shift away from  the simplistic hope of a singlecause and a single treatment for the pain. Instead, many researchers believe  that pain localized  in the vulvar vestibule requires a holistic perspective: the belief that targeting just the  multifaceted vulvovaginal pain is inadequate.  The pain can be explained only by considering other processes occurring in the body. 

In the early days of patient evaluation, we were armed only with visual inspection, a Q-tip, the patient’s reported pain scale, with very limited knowledge about the vulva, the vestibule, the vagina, and the neurology of pain perception. Today, more health care providers are aware of the global impact of vulvovaginal pain on women’s lives, and researchers are making heroic efforts not only to understand possible causes, but also to evaluate the treatments that have been used up till now and to seek out new treatments that are based on solid evidence. Many topical and oral treatment methods previously thought to be effective for vulvodynia (at least to some extent), are now shown not to have scientific support for efficacy. Currently, studies are being assessed more stringently for validity; randomized controlled trials are encouraged, and consensus on core outcome domains for vulvodynia, that will improve the ability to perform meta analyses, is being sought.¹² 

It is no small accomplishment that after forty years of confusing research, there is strong evidence that the vulva and vagina have unique inflammatory and immunological properties. Also, specialized immunological blockers (lipids produced endogenously within the body), hold promise as a vestibulodynia treatment by resolving inflammation without impairing the host defense system.³

Studies on brain functioning are clarifying understanding of pain in all spheres of human experience.

The following section, Pain Basics, provides a simple groundwork for better understanding of how pain works in general and also in the vulva and vagina. 

 

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It is no small accomplishment that after thirty years, strong evidence that the vulva and vagina  have the long expected unique inflammatory and immunological properties. Also, specialized immunological blockers  ( lipids produced endogenously within the body), hold promise as a vestibulodynia treatment by resolving inflammation without impairing the host defense system.⁴

Here, we endeavor to explain as much as possible about vulvovaginal pain.

 DEFINITIONS AND TERMINOLOGY

Multiple professional societies try to contribute clarity to the process of diagnosis by creating terminology and classification systems, but this process can culminate in confusion as well as diagnosis codes. The Diagnostic and Statistical Manual of Mental Disorders (DSM-5), published in 2013, is the primary authority for psychiatric diagnoses.⁶ is located in this compendium of psychiatric illnesses under the category of sexual dysfunctions and includes the previous terms “dyspareunia” and “vaginismus.” Vulvodynia is ostensibly there as a subset of dyspareunia, though not specifically so. Viera-Baptista, et al and others^{7 8} warn that there is room for misinterpretation and misunderstanding in this DSM-5 designation, saying, vulvodynia “…is not to be considered a sexual dysfunction, but rather a chronic dysfunctional pain disorder. Dysfunctional pain is defined as a disease state of the nervous system, which arises by its abnormal function, in the absence of neural structural damage.” They also point out that, “vaginismus” and “dyspareunia,” located together, can lead to confusion about the conditions and their therapeutic approaches.⁹ Bergeron, et al consider that this new categorization actually broadens the scope of definition for vulvodynia, as it allows for vulvar pain, deep pain, and pelvic pain on penetration.¹⁰ They mention other pain classification systems that include vulvodynia. The International Association for the Study of Pain (IASP) lists vulvodynia under “chronic primary visceral pain” within subcategories of pelvic pain.¹¹

The 11th revision of the International Statistical Classification of Diseases and Related Health Problems has included vulvodynia within the chronic pain syndromes for the first time.¹²

 

The addition of “potential associated factors” to the terminology initiated the deeper study of vulvodynia as a multifactorial process. We have adapted the definitions or rearranged tables below for the purpose of this document, but have stayed true to the intent of the original consensus statement. 

 

In the 2015 consensus statement, three pain categories were identified, along with “descriptors” related to characteristics of the pain.

 

1.Vulvar pain related to a recognizable disorder (such as infection, dermatosis, estrogen deficiency, or other identifiable condition) (see Table K1 below), 

 

OR

 

2. Vulvodynia:  vulvar pain of at least 3 months duration in the absence of clinically identifiable disease, (with possible associated biomedical and psychosocial factors),

 

OR

 

3. Pain with both a specific disorder (e.g. lichen sclerosus) and vulvodynia.

 

Although originally allocated to the diagnosis of vulvodynia alone, the following descriptors apply to both known conditions causing vulvar pain (especially those causing dyspareunia) AND to vulvodynia. ^{13 14}

•  Localized (e.g. vestibulodynia, clitorodynia) or generalized or mixed (localized and generalized) 

• Provoked (e.g. insertional, with contact) or spontaneous (without touch), or mixed (provoked and spontaneous)

• Primary: with first tampon use or attempt at sexual penetration or secondary: developing after a period of comfortable penetration^{15 16}

•  Temporally intermittent, persistent, constant, waxing and waning, immediate, delayed, etc.

Associated biomedical and psychosocial factors that may contribute to vulvodynia have been identified (see following list) and form the basis of research into causes.¹⁷ These factors may also be seen as determining recognizable subgroups that may benefit from different treatment modalities.^{18 20} is strongly associated with female sexuality, and is therefore highly impactful for patients and their partners. Women and girls of all ages can be affected but most are in younger age groups, a high proportion under 25 years.^{21 22} Studies of childhood vulvodynia are few; in many cases, persistent pain is found to have an underlying cause. Despite the pain, the majority of women continue to have sex.²³ Dyspareunia in postmenopausal (and 

 

 

 

 

 

 

 

 

It is gratifying to lessen pain for one who suffers, and equally disturbing to be unable to help. Pain management of vulvovaginal disorders often entails, for clinicians, a comprehension beyond the level provided in their education or professional experience. Indeed, even clinicians very experienced in diagnosing and treating patients with vulvovaginal complaints are flummoxed by the problem of persistent pain. 

The following section, Pain Basics, provides a groundwork for better understanding of how pain works in general and also in the vulva and vagina. 

Introduction

In 1976, vulvar pain was officially recognized by the International Society for the Study of Vulvovaginal Disease (ISSVD) with the term “burning vulva syndrome.”

The 2003 ISSVD Terminology and Classification of Vulvodynia divided vulvar pain into two major groups:

1. vulvar pain related to a known disorder
2. vulvar pain in the absence of relevant visible finding or clinically identifiable disease.⁹⁵ This second group is termed vulvodynia

Vulvodynia was divided by location to generalized or localized, depending on the distribution of the pain, and in 2012, further sub-typed into provoked, unprovoked, or mixed pain.

Further understanding of vulvar pain and vulvodynia comes with the recent update on pain definitions from the ISSVD, presented in its entirety.

2015 ISSVD Consensus Terminology and Classification of Persistent Vulvar Pain

Table 1: 2015 Consensus Terminology and Classification of Persistent Vulvar Pain

A. Vulvar pain caused by a specific disorder*

• Infectious (e.g. recurrent candidiasis, herpes)
• Inflammatory (e.g. lichen sclerosus, lichen planus, immunobullous disorders)
• Neoplastic (e.g. Paget disease, squamous cell carcinoma)
• Neurologic (e.g. post-herpetic neuralgia, nerve compression or injury, neuroma)
• Trauma (e.g. female genital cutting, obstetrical)
• Iatrogenic (e.g. post-operative, chemotherapy, radiation)
• Hormonal deficiencies (e.g. genito-urinary syndrome of menopause [vulvo-vaginal atrophy], lactational amenorrhea

B. Vulvodynia – Vulvar pain of at least 3 months duration, without clear identifiable cause, which may have potential associated factors

Descriptors:

• Localized (e.g. vestibulodynia, clitorodynia) or Generalized or Mixed (Localized and Generalized)
• Provoked (e.g. insertional, contact) or Spontaneous or Mixed (Provoked andSpontaneous)
• Onset (primary or secondary)
• Temporal pattern (intermittent, persistent, constant, immediate, delayed)

*Women may have both a specific disorder (e.g. lichen sclerosus) and vulvodynia

Table 2: 2015 Consensus Terminology and Classification of Persistent Vulvar Pain – Appendix: Potential Factors Associated with Vulvodynia*

• Co-morbidities and other pain syndromes (e.g. painful bladder syndrome, fibromyalgia, irritable bowel syndrome, temporomandibular disorder) [Level of evidence 2a]
• Genetics [Level of evidence 2b]
• Hormonal factors (e.g. pharmacologically induced) [Level of evidence 2b]
• Inflammation [Level of evidence 2b]
• Musculoskeletal (e.g. pelvic muscle overactivity, myofascial, biomechanical) [Level ofevidence 2b]
• Neurologic mechanisms:
• Central (spine, brain) [Level of evidence 2b]
• Peripheral [Level of evidence 2b]
• Neuroproliferation [Level of evidence 2b]
• Psychosocial factors (e.g. mood, interpersonal, coping, role, sexual function) [Level of evidence 2b]
• Structural defects (e.g. perineal descent) [Level of evidence 2b]

*The factors are ranked by alphabetical order

 

Further interpretation of  the 2015 pain classification

Since 1976, clinicians have designated any persistent vulvar pain that they were unable to diagnose as “vulvodynia.”

Now, in 2019,  it is recognized that there are a number of accepted causes of vulvar pain, as well as a number of other probable causes of vulvar pain needing further evidence to become accepted.  Thus, the new title Consensus Terminology and Classification of Persistent Vulvar Pain moves away from pain of unknown cause (vulvodynia) and gives clinicians  a number of possible sources to explore in a workup before giving the diagnosis of vulvodynia. As our understanding of vulvodynia evolves beyond the rudimentary classifications of localized provoked vulvodynia and generalized vulvodynia, nomenclature will be based on a clearer understanding of disease phenotype with improved diagnostic reliability and better-defined disease models.⁹⁶

Terms no longer in use include: essential vulvodynia, dysesthetic vulvodynia, burning vulva syndrome, vestibular adenitis, vestibulitis, vulvar vestibulitis syndrome, and vestibulodynia (although this last term may persist). Clinicians need to be aware of these labels because they appear in studies done prior to 2015.

Localized provoked vulvodynia (LPV) is most common, especially in premenopausal women⁹⁷, ⁹⁸ while generalized vulvodynia is more common in peri-and postmenopausal women⁹⁹.

Etiology of pain caused by a specific disorder

Vulvar pain from a specific disorder is caused by the pathology of that disease. Table K-1 Possible causes of vulvovaginal pain from specific disorders and associated annotation links lists the known causes of vulvar and vaginal pain. These recognizable disorders can be identified by the process laid out in our algorithm: careful history that includes review of symptoms (Annotation A), attention to possible systemic or autoimmune diseases or history of atopy, sexual history, psychological profile (Annotation B), lifestyle issues (Annotation J),  targeted non-genital and genital exams (Annotation C) (Annotation D), including assessment of vulvar architecture (Annotation F) and skin (Annotation H), pain and symptom mapping (Annotation I), evaluation of tolerance for the exam (Annotation D), the vagina (Annotation N) (Annotation O) and the pelvic floor (Annotation L), and evaluation of vaginal pH and secretions through wet prep and other tests (Annotation P).

By taking these steps, which may include testing such as STI testing and yeast culture (Annotation P) or vulvar or vaginal biopsy (Annotation G), disorders that the clinician may not even be aware of will be discovered and can then be treated. It is hoped that treating the condition will also treat the pain. This is not always the case. Because of the pain mechanisms described in Pain Basics, pain sometimes persists despite treatment: a specific disorder and vulvodynia can co-exist.

Table K-1 Possible causes of vulvovaginal pain from specific disorders and associated annotation links

Etiology of pain from vulvodynia

Vulvodynia is, by definition, idiopathic, without known etiology. On exam, the genitalia usually look normal. There may be some erythema, especially with gentle touch with a Q-tip. The patient feels pain with touch out of proportion to any abnormality that can be seen with the naked eye or with a magnifying glass. It is, therefore, a diagnosis of exclusion; a clinician must be able to say that the pain is not caused by a specific disorder (Table K-1). However, it is prudent to look for increasingly recognized potential factors associated with vulvodynia.  (See Table K-2)

Table K-2 Potential factors associated with vulvodynia and associated annotation links

A pain syndrome that may be a form of vulvodynia or may be vulvar pain from a (known) specific cause is pudendal neuralgia (PN). Pudendal neuralgia is defined as a syndrome of neuropathic pain in the distribution of the pudendal nerve. It was at one time definitely considered a cause or type of vulvodynia,¹⁰⁰ but the increase in knowledge over the past two decades has more clearly defined PN as pain from a known specific cause of vulvar pain-the pelvic floor muscles. More evidence is needed; there is no evidence to support the automatic diagnosis of pudendal entrapment when the pain in the area supplied by the pudendal nerve is present.

The cause of the PN is not always clear, but it is believed to result from nerve injury caused by stretching or compression. ¹⁰¹ Such injuries include fracture of the pelvis (ischial spine), entrapment of the nerve on its route adjacent to the ischial spine, between the sacrotuberous and sacrospinous ligaments,¹⁰² or by compression of the nerve as it courses through Alcock’s canal. The nerve may sustain injury from cycling,¹⁰³ infectious damage by herpes simplex,¹⁰⁴ tumors, or chemoradiation. The nerve may be damaged by stretching from chronic constipation, perineal descent, or fetal descent in second stage labor. Iatrogenic injury may result from pudendal nerve blocks, following transobturator inside-out tape procedure,¹⁰⁵ following transvaginal mesh surgery, ¹⁰⁶ sacrospinous ligament fixation, or as damage to the nerve or its blood supply during any type of surgical intervention requiring exploration of the pelvis. Traction on the lower extremities for orthopedic surgical procedures on the fracture table has also been suggested to be a cause of PN.¹⁰⁷ Acknowledging the transitional status of pudendal neuralgia, we have put the condition in both Table K1 and K2.

Likewise, we have placed psychosexual issues leading to poor sexual arousal and vaginismus on both lists. We have worked with women who have been able to understand that overactive pelvic floor muscles are causing involuntary tightening of the vagina, who have had resolution of what was thought to be vulvodynia. It is important for clinicians to understand, however, that, if they see nothing “abnormal” on exam, vaginismus is not a “given” diagnosis.

As more is learned about the causative factors associated with vulvodynia, those factors, with the proper evidence, will move up to the category of vulvar pain from a specific disorder.

Inflammation

Vulvodynia as an inflammatory condition has been extensively debated. The vulvar vestibule is derived from endoderm and therefore has immunology similar to the mucosa of the gastro-intestinal tract. Study of  vulvar immunology provided some insight into LPV. In localized provoked vulvodynia (LPV) different vulvovaginal infections, such as recurrent candidiasis as well as urinary tract infections, have been considered as risk factors for disease.^{108 109 110} A localized hypersensitivity to Candida (yeast) has been described in LPV.¹¹¹

Histopathology from the vulvar vestibule has often shown increased lymphocytic infiltrates in the vestibular mucosa.^{112  113} But the characteristics of the inflammatory response have never been well elucidated. Since several studies have found no evidence of classic active inflammation, there has been a tendency to abandon inflammation as a source of pain in the vulvar vestibule.^{114 115}

Instead, attention has focused on exaggerated inflammatory response; dysregulation of inflammation in affected women has been suggested.^{116 117 118 119}

The vestibular mucosa of LPV patients characteristically has an increased number of exceptionally superficial nerve endings.¹²⁰  One study suggested that an increased number of mast cells producing heparanase enzyme boosts nerve growth.¹²¹ However, the role of mast cells has not been fully proven.¹²² A recent study has shown no increase in mast cell density in patients with confirmed vulvodynia versus racially matched controls.¹²³

 As the immune and neuronal systems are often closely interrelated, an increased inflammatory response may well predispose to the development of a pain syndrome such as LPV.¹²⁴

Researchers recently focused on the characteristics of the local immune system by immunohistochemical analysis of different immune cell types in the vestibular mucosal tissue. In  27 LPV patients and 15 controls, they demonstrated the presence of key immune players and found evidence of immune activation in LPV.¹²⁵

Mucosal surfaces of the human body are known to contain secondary lymphoid tissue, the mucosa-associated lymphoid tissue (MALT).¹²⁶  In MALT, B and T lymphocytes organize to form germinal centers, which play a central role in initiating an immune response against foreign antigens such as those from viruses and bacteria. The crucial point in the initiation of an immune response is the presentation of foreign antigens to T lymphocytes. Macrophages, dendritic cells (DCs), and B cells are called professional antigen-presenting cells. With antigen presentation, the T cells become activated. The activated T cells, in turn, are capable of activating a whole range of immune cells to mount different types of responses depending on the nature of the initial insult. This part of the activation of an adaptive immune response takes place in germinal centers. A proportion of the activated cells are B cells developing into antibody-producing mature plasma cells. In mucosal areas, B cells switch into plasma cells producing dimeric IgA-class antibodies that will subsequently be transported across the epithelium to the mucosal surfaces.

More B lymphocytes and mature mucosal IgA-plasma cells were found in patients than in controls (  P  < .001 and  P  < .001, respectively). In LPV samples, B and T cells were arranged into germinal centers representing local immune activation. Germinal centers were not seen in controls. Antigen-presenting CD163  (DCs) and CD68 macrophages were found both in patients and controls with similar densities. DCs were found to extend their dendrites into the luminal space through an intact epithelium. Similar amounts of mast cells were found evenly scattered throughout the stroma of vestibular mucosa of both patients and controls.

Thus, the vestibular mucosa seems to have its own organized immune system that could be called VALT, similar to other endoderm derived mucosal surfaces of the human body containing secondary lymphoid tissue, called MALT.¹²⁷ Furthermore, the findings of germinal centers and large numbers of B cells and plasma cells support immune activation in LPV. In contrast, other types of immune cells, like macrophages and mast cells, were present in equal densities both in the patient tissues and healthy mucosal tissues.¹²⁸

More concrete evidence in support of the unique, embryologically defined, inflammatory/immunologic responsiveness in the vulvar vestibule was demonstrated in a study of fibroblast strains derived from two regions of the lower genital tract in LPV cases and pain-free controls. The fibroblasts were challenged with six separate stimuli: live yeast species of Candida albicans, C. glabrata, C. tropicalis, S. cerevisiae, yeast extract (zymosan), or an inactive vehicle. Production of prostaglandin E2 (PGE2) and interleukin-6 (IL-6) were measured as pro-inflammatory markers. Highest IL-6 and PGE2 occurred with vestibular fibroblast strains following C. Albicans, C. glabrata, and zymosan challenges. Researcher believe that this enhanced site-specific innate immune responsiveness to yeast pathogens by fibroblasts may be an early step in LPV pathogenesis. ¹²⁹

Further support of the fundamental role of inflammation and immune activation in LPV comes from a study of vestibular mucosal specimens from 17 patients with LPV and from 15 controls. Excessive epithelial nerve growth in LPV was associated with increased B cell inflammation.¹³⁰

Disorder of the central nervous system/other pain syndromes

There is increasing recognition that vulvodynia may be a disorder of the central nervous system because:¹³¹ (1) It is chronic pain and this, by definition, involves changes in the central nervous system, perpetuating the pain through central sensitization.¹³² (2) Women with vulvodynia have an increased incidence of other chronic pain syndromes,¹³³ (3) Vulvodynia patients have evidence of systemic sensory dysregulation with increased perception of noxious stimuli not only at the vulva but also at sites distant to the genitalia.¹³⁴,¹³⁵ In addition, chronic pain is a disease process itself and does not need to be validated by a visible cause, such as a lesion. Although there may be a triggering source of pathology, the mechanisms that perpetuate the pain result primarily from central nervous system changes (or plasticity) as central sensitization occurs.

Pain and the brain: stress

The pain of vulvodynia probably results from more than one cause, or a combination of factors–all of which differ from woman to woman–and all best understood within the framework of what neuroscience has discovered: that there is a entire system of mind-brain-body interactions related to genetic and psychosocial risk factors, biological and/or infectious triggers, coping skills, and personality traits that affect how the brain perceives, processes and manages pain. None of these studies supports causality, but at times, the absence of identifiable physiologic pathology has led to the view that the pain may be solely due to psychological factors. This position may be as erroneous as emphasizing only the physiological aspects of the conditions.¹³⁶

In response to stressors of the external and internal environment, the body produces hormonal and neurotransmitter mediators that turn on cellular and tissue responses throughout the body, and lead to coordination of physiological response to the circumstances at hand.¹³⁷ Research has reinforced the fact that classic “fight or flight” stress mediators have protective as well as damaging effects. As researchers endeavor to discern which mediators protect and which damage, a new formulation addresses the relationship between challenges from the environment and biological response.

In place of the ambiguous term stress, two new concepts have been formulated. Allostasis represents the brain’s constant effort to process daily physical, environmental, social and psychological stressors and return the body to a steady state of balance or homeostasis. With allostasis, there is stability, or homeostasis, during change. Allostatic load refers to the wear and tear that the body experiences from repeated cycles of allostasis, as well as the inefficient ignition or shut down of these responses. ¹³⁸ When the body is unable to return to homeostasis, allostatic load increases and is manifested as loss of resilience and increased risk of disease. Fear, including social fear, is a significant trigger of the stress response¹³⁹ and a source of allostatic load. ¹⁴⁰

Repeated exposure to stress either through early or chronic exposure causes wear and tear on the body’s ability to sustain balance and resilience. It is possible that stressful or traumatic life events in the past may “prime” the brain to contribute to the onset of pain. Adverse life events such as destructive relationships, parental divorce or adverse childbirth experiences are more frequent in women with vulvodynia than in women without.¹⁴¹

In a population based study, women with vulvodynia were 2.6 times more likely to report lack of family support (comfort, encouragement and love). Women who developed vulvodynia as adults were significantly more likely to report childhood abuse, (physical or sexual) than age matched controls. ¹⁴²

The brain can actually be remodeled to be less efficient at restoring homeostasis. Demonstration that women with chronic vulvar pain have differences in their brain anatomy compared to age matched controls supports the concept of the brain as an important modulator of pain in women with vulvodynia. ¹⁴³ In chronic pain patients, a tendency to focus on pain (attentional bias) increases pain, disability and distractibility.¹⁴⁴

Altered levels of stress hormones and other neurotransmitters affect our thoughts, actions and emotions. ¹⁴⁵ Catastrophizing refers to predicting negative outcomes and assuming that the negative outcome will be catastrophic. Catastrophizing is associated with depression and anxiety, two significant predictors of vestibular pain in postmenopausal women with painful intercourse. Estrogen levels were not predictive. ¹⁴⁶

The majority of women with provoked vulvar pain are highly stressed.¹⁴⁷¹⁴⁸ Stress is under consideration as an important etiologic factor in vulvar pain¹⁴⁹ since, in the rodent, it actually alters the brain through microglial proliferation in the hippocampus and substantial nigra,¹⁵⁰ the same areas that show increased gray matter density inwoven with provoked vulvodynia compared to controls.¹⁵¹ The gray matter density was related to the women’s clinical symptoms as measured by their pain thresholds at the introitus. Rosemary Basson’s model in Figure 2 depicts the increased allostatic load resulting from the build-up from stress to pain sensitization, sexual dysfunction, and further stress.

Figure 2: Circular model of provoked vestibulodynia ¹⁵²

Figure 2: Circular model of provoked vestibulodynia to illustrate the compounding effects of subsequent sexual dysfunction on overall allostatic load: emotional distress associated with premorbid anxiety, depression, traits of catastrophization, harm avoidance, hyper-vigilance, self-dislike, perfectionism may be associated with neuroplastic changes in the central nervous system leading to central sensitization and pain amplification. Feelings of being sexually substandard compound the etiological factors and lessen sexual motivation and response. Pain-induced cognitive changes may impair processing of sexual stimuli generally and at the time of sexual activity. Motivational changes associated with chronic pain circuitry may further impair sexual motivation. Stress responses of body and skin add t0 the skin pathophysiology.

Resilience describes a healthy body able to rebound from stress and disease. A number of attitudes and behaviors have been shown to strengthen the body’s ability to sustain or restore resilience and buffer against allostatic load. Acceptance, optimism, humor, cognitive flexibililty, religion/spirituality, altruism, social support, moderate physical activity/exercise are among them.¹⁵³ These skills can be learned and are recognized as making a difference in people’s lives.¹⁵⁴

Emerging research of two psychological therapies, Cognitive Behavioral Therapy (CBT) and mindfulness, suggests benefit to both pain and to sexual dysfunction.¹⁵⁵ Control of pain to eliminate its negative reinforcement on sexual function is a logical first step.

Waning pain theories

Oxalates

Use of a low oxalate diet with calcium citrate to bind oxalate excreted in the urine gained attention based on a single case of vulvodynia successfully treated with the protocol.¹⁵⁶ Subsequent studies provided no validation.^{157 158} Currently, there is no justification for evaluation and treatment of hyperoxaluria in women with vulvodynia due to its low yield and economic burden.¹⁵⁹ It is important to recognize that some of the foods high in oxalates are similar to foods to be eliminated as bladder irritants. There may be value in a trial of eliminating known bladder irritants in women who report urinary symptoms as part of their pain. These include foods high in acidity (tomatoes, alcohol, or foods with citric acid), chocolate, caffeine, artificial sweeteners, and spices.¹⁶⁰

Human papilloma virus (HPV)

There is now  little support for the idea that HPV might be related to vulvodynia. In 135 cases compared with 322 controls without pain: HPV DNA was found in 29.6% cases and 23.9% controls (RR1.4; 95% confidence interval).¹⁶¹ Treatment for warts with topical medication or surgical excision, however, may be a source of pain.

Pruritus in relation to vulvovaginal disorders

We now know that the sensation of itch and nociception cannot be equated with each other. The once popular theories that itch is based on a specific pattern of action potentials running through pain pathways or that itch results from the combination of other primary sensory signals, have now fallen out of favor.¹⁶² The confirmation of long-denied existence of central itch-specific neuronal pathways in the human supports the concept that the sensation of itch and nociception represent distinct sensory systems.^{163 164 165}

• 1 – Pruriceptive pruritus involving stimulation of the free nerve endings of a subset of nociceptive C-fibers in the skin. The sensation is transmitted to the dorsal horn of the spinal cord, then up the spinothalamic tract to the cerebral cortex for processing.
• 2 – Neuropathic pruritus, cased by damage of the itch-transmitting afferents of the peripheral nerves or the spinal cord, e.g., postherpetic pruritus.
• 3 – Neurogenic pruritus, arising because of disease of central structures of the CNS such as brain tumors or abscesses.
• 4 – Psychogenic pruritus based on metabolic disorders in the CNS. Type 1 is the type involved in inflamed skin.

In the skin, many factors contribute to the induction, exacerbation, or suppression of pruritus. Physical stimuli such as heat and cold modulate the perception of itch; painful heat and cold can significantly diminish it, whereas moderate cold intensifies itching.¹⁶⁶ Mechanical factors such as rubbing or scratching can briefly suppress itch by activating nerve fibers that selectively activate and de-activate brain centers.¹⁶⁷ The most important factors, however, are mediators that directly induce itch by binding to pruriceptors or, indirectly, by releasing products that induce other cells to release pruritogenic substances: e.g., histamine from mast cells, interleukin-31 from T cells, or nerve growth factor from eosinophils and keratinocytes.¹⁶⁸

Both the peripheral and central nervous systems play an important role in the perpetuation of itching. A number of inflammatory mediators directly activate pruritus-mediating nerve fibers, and some of these mediators can also produce long-term changes in the skin. For example, significantly elevated levels of Nerve Growth Factor and Substance P cause increase in cutaneous itch fibers, adding to the intensity and chronicity of the pruritus.¹⁶⁹

Vulvovaginal pain related to a specific disorder

The most common areas of the vulva involved with pain include: discomfort with separation of the labia minora, dyspareunia from pain on penetration through the vestibule, and point tenderness localized to area surrounding the Skene gland orifices or the Bartholin gland openings within the vulvar vestibule.¹⁷⁰

The manifestations and symptoms of each of the conditions in Table K-1 are described under the annotation indicated by the letter in parentheses. Diagnosis of each condition is included in the annotation.

Each known cause of vulvovaginal pain has its unique constellation of clinical manifestations. Pattern recognition is key: training the ear to listen for a history of irritative vaginal secretions, dyspareunia, or pain suggesting one of these categories, and training the eye to detect the presence of architectural abnormalities or epithelial lesions of the vulva or vagina are the challenges of vulvovaginal diagnosis.

Generalized vulvodynia: symptoms

Generalized vulvodynia refers to burning, stinging, soreness, pain, irritation, or rawness anywhere on the vulva, perineum, or peri-rectal area. It is usually sudden in onset, and can occur at any age. It may be provoked (brought on by touch, movement, sexual activity) or spontaneous (spontaneous, without any obvious trigger), or a combination of both (mixed). The pain may be constant or sporadic, present for hours, days, weeks, then regressing. It may be diffuse without clear borders, or focal, or may alternate in location. Women seldom use the word vulvodynia, or even the word pain; instead they describe burning, stinging, soreness, and irritation. They often have trouble localizing the site and explaining what they feel. They use various descriptors for the sensations:

“Deep aching”

“Feels like sand paper”

“Feels like my pubic hair is being pulled”

“Rawness, “rug burn”

“Sitting on a cactus”

“Tennis ball wedged in the vagina”

“Feels like there are insects crawling underneath the skin”

“Zapping, shooting” (paresthesias)

“Constant awareness of vulva, vagina”

Women often describe urinary symptoms such as burning, frequency and urgency but urine cultures are negative.

Any pressure stimulus on the vulva can worsen the pain: tampon insertion, sexual intercourse, speculum insertion, tight clothing, biking, horseback riding, sitting, walking, and exercising.

Localized vulvodynia: symptoms

Women often give clues that they may have localized provoked pain. Pain often starts out as being provoked, but persists as spontaneous or both provoked and spontaneous pain.

“Intercourse has never been comfortable for me” or “Recently it started to hurt”

“I have never used tampons because they hurt” or “Lately I can’t use tampons”

“I’m just too small.” or “My partner is too large.”

“You must use your smallest speculum” or “I have always had a problem with the speculum.”

“I keep having infection- yeast, BV, yeast, BV”

A recent study aimed to determine whether there are differences in the clinical presentation of symptoms and vulvar pain ratings in postmenopausal women compared with premenopausal women with provoked vestibulodynia (PVD) enrolled in a clinical trial, after correcting for estrogen deficiency. Researchers found that pre-and postmenopausal women with PVD have similar pain scores, and with the exception of a higher incidence of burning in postmenopausal women, similar presenting clinical symptoms. The statistical power of the study was limited by the small number of postmenopausal women in it. ¹⁷¹

 

Pudendal neuralgia: symptoms

Pain occurs over the sensory distribution course of the pudendal nerve: in the vagina, vulva, labia, mons, and clitoris. Symptoms of pain and paresthesia may extend as far as the groin, inner leg, buttocks, and abdomen.¹⁷² The pain and paresthesia may be perceived in only one of these areas, in several, or in all of them, and the pain may vary in location from time to time. It often starts in one place and progresses; usually it is unilateral. The symptoms may, however, be bilateral or worse on one side than the other.

The varied presentation of PN may reflect the nerve’s mixed functions (motor, sensory, autonomic) and its multiple branches with anatomic variations.¹⁷³

Patients report beginning the day in relative comfort, with pain increasing gradually over the day. Sitting significantly exacerbates the pain. By day’s end they are often miserable; falling asleep may be difficult. Although they awaken in the night for another reason, the pain itself does not disturb sleep.¹⁷⁴ Sitting on the toilet seat often brings some relief by lessening the pressure on the nerve. Extreme sensitivity to light touch (hyperesthesia) restricts clothing to none at home and loose pants and skirts when out. Constipation, often exacerbating pain after bowel movement,¹⁷⁵ urinary frequency, urgency or hesitancy,¹⁷⁶ and vulvar, perineal or rectal pain during or after intercourse,¹⁷⁷ are all associated.

A typical case begins with remissions and relapses, evolving to a chronic and progressive course,¹⁷⁸ completely disruptive of day-to-day living, relationships, and sexual function.

Generalized spontaneous vulvodynia: work up

A full work up is necessary to determine if the source of these descriptions comes from any of the conditions in Table K-1 and is therefore pain related to a specific disorder. Pain mapping (Annotation I: Pain and symptom mapping and the Q-tip test) will identify the involved areas. In the case of generalized vulvodynia, there will be no other physical findings other than possible erythema. The combination of the history, the pain map showing generalized distribution, and the lack of any findings to suggest a known disorder (this may require more than one visit), leads to the diagnosis of generalized spontaneous vulvodynia. Remember that there may be more than one problem. Pain located in a different location from the area affected by infection or dermatosis, may suggest vulvodynia in addition to the vulvar pain from the infection or dermatosis. For example, a woman with multiple, pruritic syringomas of the labia majora also has spontaneous burning in the vestibule from vulvodynia. Whether the two problems are related is still unclear.

Localized provoked vulvodynia: work up

Friedrich’s criteria ¹⁷⁹ have traditionally been used for diagnosis of localized provoked vulvodynia:

Severe pain on vestibular touch (Q-tip test) or attempted vaginal entry

Tenderness to pressure localized within the vulvar vestibule

Physical findings confined to vulvar erythema of various degrees.

However, since localized vulvodynia may also be spontaneous, these criteria are now only partially accurate. As with generalized vulvodynia, a full work up is necessary to determine if the source of these descriptions comes from any of the conditions in Table K-1 and is, therefore, pain related to a specific disorder. Localized pain in the vestibule may be the first condition that comes to mind, but scarring from undiagnosed lichen sclerosus (Atlas of Vulvar Disorders), chronic inflammation from inflammatory vaginitis (Annotation O: the vaginal epithelium), or burning from the innumerable causes of pelvic floor hypertonicity (Annotation L: the pelvic floor) reflected in the vestibule, are a few of the possibilities. It is important to note that the presenting symptoms of lichen planus are soreness and burning. Classic erosions and reticules are not always seen. Primary or secondary vaginismus (Annotation D: patient tolerance for exam) (Pelvic floor dysfunction/vaginismus)may also be involved.

In the absence of any spontaneous discomfort, and with tenderness to pressure and touch (Q-tip test) in a focal area (often the vestibule) without identification of any known cause, localized provoked vulvodynia is diagnosed.

Pudendal neuralgia: work up

The diagnosis of PN is a clinical diagnosis of exclusion after ruling out other causes of symptoms (Table K-1). Clinical diagnostic criteria for PN developed by a multidisciplinary working party which met in Nantes, France in September, 2006 (Nantes criteria¹⁸⁰) include five essentials:

(1) pain along the anatomical distribution of the pudendal nerve;
(2) pain aggravated by sitting;
(3) the patient is not awakened at night by the pain;
(4) there is no objective sensory loss on clinical examination; and
(5) the pain is improved by an anesthetic pudendal nerve block.

Physical examination is usually normal. The most constant element on physical examination is a replication or worsening of the pain during rectal or vaginal digital pressure in the area of the ischial spine.¹⁸¹ Although this may occur in an asymptomatic woman, unilateral tenderness in this location suggests PN by the Nantes criteria.¹⁸²

Clinical neurophysiology tests have low diagnostic efficacy and must be considered to only be complementary investigations. Nerve response time that is slower than normal (<2.2 ms) by pudendal nerve motor latency testing (PNMLT) may¹⁸³ indicate nerve damage but is not considered a highly sensitive test. PNMLT tests only motor function; currently no modality exists for sensory testing of the pudendal nerve.

Differential diagnosis includes the specific causes of pain in (Table K-1), tumor in any location impinging on the pudendal, ilioinguinal or genitofemoral nerves, diabetic neuropathy, viral infection (herpes simplex, herpes zoster, HIV), multiple sclerosis, and pathology of the spine. Tarlov cysts are meningeal cysts located in the sacral region. These cysts are usually considered incidental findings on MRI, but may cause sciatica or perineal pain resembling pudendal neuralgia. Some studies suggest that up to 50% of patients with Tarlov cysts may have perineal pain.¹⁸⁴ Symptomatic Tarlov cysts should correlate with the location of pain.

Introduction

Vulvar pain from a known disorder often resolves with treatment or control of the condition, but in some cases, treatment of the pain is necessary in addition to treatment of the disorder. Currently there is no standardized treatment for vulvodynia. A systematic literature search concluded that comparison of clinical trial results in vulvodynia is not possible because of a lack of standard treatment outcome measures. The authors recommended application of the IMMPACT criteria to guide the development of a minimum core set of standard outcome measures.¹⁸⁵

A review of the available clinical therapies for vulvodynia management also revealed new data implicating pro-inflammatory mediators pain elicitation. The authors emphasize that acceptance of inflammation as a possible contributing factor to the occurrence of vulvodynia opens a new view of possibilities for treatment and management with the use of agents to block pro-inflammatory mediator production.¹⁸⁶.

Approach to the patient

Vulvar pain from a known disorder, as stated above, may resolve with treatment or control of the condition, but in some cases, treatment of the pain is necessary in addition to treatment of the disorder. Vulvodynia, by definition, pain of unknown cause, has no standardized treatment and definitely no one-size-fits-all treatment. Well-conducted studies of vulvovaginal pain of any type are few, and the level of evidence is low. Randomized controlled studies are rare, whereas case-control studies and clinical observations are common.¹⁸⁷ Faced with debilitating problems, clinicians work with available information and reliance on clinical experience, sometimes despite current study information. As one expert expresses, “They (the tricyclic antidepressants) are extremely useful in managing the neuropathic component of vulvar pain. Despite a recent, apparently well-conducted study showing lack of benefit, my 25 years of personal clinical experience with tricyclics convince me that I should wait for follow-up studies before abandoning this therapy.”¹⁸⁸

Patients with any chronic pain are often frustrated and anxious. Vulvar pain and vulvodynia, with their impact on a woman’s femininity and sexual function ( Vulvar pain and sexuality), are no exception. Women with vulvar pain and vulvodynia have failed many treatments and have seen many physicians.¹⁸⁹ They need to be reassured that their symptoms are real, and that treatment is available for this complex set of disorders.¹⁹⁰ Treatment must be individualized. Women, and their partners, also need to understand that there is no single modality to “fix” the problem; often, it is the combination of a variety of approaches that brings amelioration. A multidisciplinary team approach is needed to address the different components of each case. Most patients need a combination of psychosexual, pharmacologic, and rehabilitative/physiotherapy-based interventions with guidance from a team that may include gynecology, physiotherapy, clinical psychology, sexual counseling, and pain specialists.¹⁹¹ Treatment choices must include involvement of the partner when appropriate, consideration of the local health care system, and attention to cost.¹⁹²

A precise timeline is not possible, and progress is slow. A woman needs a week or two (often having increased slowly over a week or two prior to that) at the therapeutic level of any medication. She may say that there is no difference, but close questioning may reveal, for example, that her pain level has gone from 7/10 to 6/10 most days. She may have had a day or two free of pain. Or, she may notice that a pain flare lasts a shorter duration. Quantified information is essential in order to see the picture and continue a potentially helpful medication. At each visit, obtain a quantified number (0-10), for highest pain level and number of days that this level exists each month. (Annotation I: Pain mapping and the Q-tip test).

Desensitization

Identify and eliminate any possible pain triggers

• Stop offending irritant activities on the vulva (Annotation J: Lifestyle issues). Although soap is an unlikely culprit, every aspect of the patient’s lifestyle must be explored for possible contributing factors.
• Diagnose and suppress any vaginitis: candida, inflammatory vaginitis, trichomonas (Annotation P: Vaginal secretions, pH, microscopy, and cultures). Remember that bacterial vaginosis is not a significant cause of pain.
• Suppress herpes if active (Centers for disease Control: www.cdc.gov/std/herpes/treatment.htm)
• Marsupialize recurrent/persistent Bartholin cysts (Atlas of Vulvar Disorders). In our experience, we have seen provoked pain in the vestibule chronically inflamed by such cysts.
• Provide adequate local estrogen if there is atrophy (Annotation O: The vaginal epithelium)
• Diagnose and treat lesions of dermatitis, dermatosis (Atlas of Vulvar Disorders)
• Recognize systemic disease such as drug reaction, Sjögren, or Crohn disease, and treat vulvar manifestations (Annotation O: The vaginal epithelium)
• Consider seminal plasma allergy if history suggests (Semen allergy: Atlas of vulvar disorders)
• Consider issues such as painful bladder syndrome, interstitial cystitis, pelvic floor dysfunction (Annotation L: The pelvic floor)
• Refer to physiatrist or physical therapist to evaluate and treat musculoskeletal problems possibly affecting pelvic floor and pudendal nerve. (Annotation L: The pelvic floor.)
• Consult experts regarding pain in other areas, (e.g., gynecologist for endometriosis, urologist for interstitial cystitis), to make sure that all components of a regional pain syndrome are addressed.
• Always ask yourself if there is any possibility of a pre-malignant or malignant lesion (Atlas of Vulvar Disorders.)

Educate about vulvar pain

Use handouts (to patient handouts), website referrals, and local support groups. Emphasize that pain may need to be managed, not cured. Describe the typical slow and gradual regression of pain that may occur. Discuss global impact on every aspect of sexuality (Vulvar pain and sexuality), emphasizing that pain must be managed first; then work on sexual function can occur. Discuss the psychology of pain, factors that worsen pain, and the importance of taking charge. Suggest Margaret Caudill’s How to Manage Pain Before It Manages You, 3rd edition. New York, Guilford Press, 2009. Offer counseling for support, anxiety, depression, or relationship problems.

Provide information about comfort measures

Flares of pain can be minimized by a variety of factors (Self Help Tips for Vulvar Skin Care: http://www.nva.org). By far, the most important comfort measure is the technique of “Soak and Seal:” sitting in comfortable water (tub, sitz bath under the toilet seat, or gentle hand held shower for 5-10 minutes twice daily). A woman who is physically unable to use the tub or sitz bath may protect the bed with plastic sheeting and use sopping wet compresses. Pat dry gently; then seal in the moisture with a film of petrolatum or mineral oil. Cool gel  packs wrapped in a soft cloth are also important to pain management. Although ice against the skin can cause frostbite, pain is significantly allayed by cold packs.

Set expectations

While the symptoms of vulvodynia may remit entirely, it is possible that they improve but do not disappear; they are managed, not cured. This is an important concept to emphasize at the initiation of therapy. There is no crystal clear cure, no magic bullet, no one-size-fits-all approach. There is improvement with time and effort.

Provide guidelines for sex

We ask women who have pain on penetration to stop vaginal intercourse until there has been some improvement in symptoms. Ongoing intercourse in the presence of pain is a negative reinforcer and can lead to secondary vaginismus. (Annotation D: Patient tolerance for genital exam). We encourage open communication between a woman and her partner about her pain with the effort to prevent feelings of rejection. We encourage intimacy and the pursuit of any mutually agreed upon pain-free alternatives to vaginal intercourse.

If sexual intercourse is possible with a level of comfort acceptable to the woman, we recommend use of a lubricant such as a few drops of plain baby oil without fragrance; this may be well tolerated as long as condoms are not being used. Latex condoms are not compatible with oil-based lubricants or medications. In women using condoms, a water-based lubricant is appropriate (e.g., an iso-osmotic, pH balanced product, e.g., Pre-Seed®). Some women find a decrease in sexual pain with use of side-lying or rear entry.

Pharmacologic treatment for vulvodynia

Topical medications: antinociceptive agents

Topical Lidocaine was previously recommended as a firstline treatment for vulvodynia based on promising results in uncontrolled trials.^{193 194} and in one controlled trial.¹⁹⁵  It was no better than placebo in another.¹⁹⁶  Since women anecdotally report that lidocaine is helpful, and given that  studies have been small, further placebo-controlled studies should be conducted before firmly recommending against lidocaine.¹⁹⁷

Women with generalized vulvodynia or vulvar pain from a known cause often benefit from lidocaine during pain or itching flares. In some cases where sexual intercourse is painful, we ask a woman to apply one teaspoon to the vestibule 10-15 minutes prior to intercourse, avoiding the clitoral area. After 15 minutes, any excess is wiped away so that it does not come in contact with her partner. Lubrication can then be added. (section on lubricants, Annotation P: Vaginal secretions, pH, microscopy, and cultures). Prior to Pap smear, colposcopy, or other procedures, the same Lidocaine application is helpful. We always ask a woman to use Lidocaine with dilators or with physical therapy treatments, if acceptable to the therapist. (Annotation D: Patient tolerance of the genital exam). Women should be warned that Lidocaine may burn on initial application, the sensation lasting about 45 – 60 seconds, before numbing takes effect. This burning, as long as it stops after the first 60 seconds, is not harmful. Lidocaine is sometimes prescribed in 2% gel form. Since this contains alcohols, it often burns more than the ointment form. Lidocaine 2.5%-prilocaine 2.5% ointment combines two amide topical anesthetics; it provides more anesthetic relief especially in the vestibule, but may cause more burning as it takes effect. Keeping the lidocaine in the refrigerator so that it is chilled can be helpful. Lidocaine ointment 5% has 50 milligrams of lidocaine in 1 gram. Use of local lidocaine should not exceed 5 g of Lidocaine Ointment USP per day, 5% containing 250 mg of lidocaine base (equivalent chemically to approximately 300 mg of Lidocaine hydrochloride). This is roughly equivalent to squeezing a six (6) inch length of ointment from the tube. In a 70 kg adult, this dose equals 3.6 mg/kg (1.6 mg/lb) lidocaine base.

A small study reports early clinical observations on the use of combination topical meloxicam 0.3% and lidocaine 5% applied to the vulva twice daily by patients with vulvodynia. Of the eight participants, six had a subjective improvement in their symptoms with the use of the combination gel. They reported between one- and four-point reductions on the Likert pain scale and mild to moderate improvement of symptoms. Common side effects reported were burning and stinging.¹⁹⁸

Other topical therapies with questionable efficacy include estrogen,¹⁹⁹moisturizers, topical muscle relaxers,²⁰⁰ capsaicin,^{201 202}

Topical tricyclic antidepressants and anticonvulsants have been reported helpful but studies are small, requiring further investigation.²⁰³²⁰⁴

Oral medications

In general, improvement with any centrally acting drug takes weeks and is uneven. Pain may seem to lessen but then return; expect a trend of slow diminution of pain, with less frequent and less intense flares.

The medications used for pain management have a number of side effects and interactions. Patient education is essential, especially in view of the fact that an unexpected side effect e.g., burning with Lidocaine or sedation with tricyclic may cause rejection of medications that could otherwise be helpful.

Tricyclics

Antidepressants such as amitriptyline, nortriptyline and desipramine, not only target pain and depression (associated with vulvodynia),²⁰⁵²⁰⁶but also have proven neuropathic pain-relieving effects.²⁰⁷

The mechanism of action of tricyclics has been thought to be related to inhibition of the re-uptake of transmitters– specifically nor-epinephrine and serotonin. It is possible that the mechanism may be more closely related to anticholinergic effects. Tricyclics affect sodium channels and the N-methyl-d-aspartate (NMDA) receptor.²⁰⁸

Tricyclic antidepressants (amitryptiline, nortryptiline, desipramine) are  considered effective compounds in the treatment of neuropathic pain, fibromyalgia, low back pain, and headaches according to meta-analyses and clinical studies of these agents retrieved through the use of MEDLINE, Google scholar, and Cochrane databases.²⁰⁹ They are a common treatment for vulvodynia.

In randomized, prospective trial, 76 women with generalized, localized or mixed vulvodynia undertook one of three treatment interventions for a period of 12 weeks: self-management, oral amitriptyline (10–20 mg/day), or topical triamcinolone plus oral amitriptyline (10–20 mg/day). The trial suggests that self-management has a modest effect and that low-dose amitriptyline (with and without topical triamcinolone) is not effective in reducing pain in women with vulvodynia.²¹⁰

Studies with higher doses of amitriptyline (40-60 mg/day) suggested that 50% or greater improvement in pain scores can be achieved for both provoked and spontaneous vulvodynia.²¹¹ Because it has been thought that doses lower than those used to treat depression could be used for pain, inadequate dosage may be a major flaw in treatment and treatment studies of tricyclics.

Emphasize to patients that tricyclics are being used for pain, not depression, although the anti-depressant effects may be useful.

Begin treatment with the less sedating nortriptyline or desipramine: 10 mg at bedtime and increase the dose by 10 mg every five days to 50 mg at bedtime. If the patient is extremely sensitive to medications, nortriptyline syrup (10 mg/tsp) can be used to help the patient acclimate to the drug side effects with small increments of dose. Patients over 65 years of age also need slower (weekly) increases. If the patient is tolerating the side effects, the dose should be slowly increased to a total maximum dose of 100 to 150 mg per day. Common reasons for treatment failure are inadequate dosage or a short duration of therapy since it takes weeks to observe an effect. We explain that the pain did not evolve overnight and is not going to disappear quickly. A tricyclic with dosage of 100 to 150 mg for three months without improvement would prompt us to move to another agent.

Both nortriptyline and desipramine are less sedating than amitriptyline and have fewer anticholinergic side effects (dry mouth, constipation, sweating, palpitations). Sedation is often transient and improves with time on the medication. Constipation is a common problem and needs proactive management to prevent rejection of the drug by the patient for this reason. A patient with irritable bowel syndrome manifested as constipation may tolerate tricyclics poorly without aggressive management: use of fiber supplements, docusate, or senna. Mild vertigo and palpitations are common. An electrocardiogram should be obtained in women over 50 years of age and should be normal prior to initiating therapy. If it is abnormal, or if the woman has a history of a cardiac arrhythmia, we suggest consultation with the patient’s primary care provider or a cardiologist. Sun sensitization can occur.

Checking with the glaucoma patient’s ophthalmologist prior to prescribing a tricyclic is also recommended.

Antidepressants

Antidepressants, such as serotonin reuptake inhibitors, are largely ineffective for vulvodynia.²¹²

Neuromodulating Agents

Gabapentin

Gabapentin (Neurontin), is FDA approved for the treatment of the neuropathic pain of post-herpetic neuralgia. It is a gamma aminobutyric acid (GABA) analogue, which was synthesized to mimic this neurotransmitter. Gabapentin binds to the α2δ subunit of voltage-dependent calcium channels in the central nervous system. It has been proven that gabapentin halts the formation of new synapses, therefore decreasing neuropathic pain.²¹³
Successful use of gabapentin for generalized vulvodynia was initially reported.²¹⁴ In another study of 152 women with generalized spontaneous vulvodynia treated with gabapentin, (64 percent) achieved resolution of at least 80 percent of their symptoms.²¹⁵ These studies were not, however, considered sufficient evidence of efficacy.²¹⁶

Gabapentin in the treatment of vulvodynia in a randomized controlled trial was not more effective than placebo on the primary outcome measure, the tampon test (a surrogate marker for dyspareunia), or on secondary outcomes: sexual intercourse pain and daily pain. A lack of gabapentin treatment effect over placebo is consistent with previous controlled studies investigating other pharmacologic treatments for vulvodynia.²¹⁷

Other studies have examined the use of pregabalin,²¹⁸  lamotrigine,²¹⁹ and carbamazepine,²²⁰ but more rigorous RCTs are needed before treatment recommendations can be made.

Other medications studied for vulvodynia treatment

Fluconazole

In the only randomized clinical trial with placebo group, Bornstein, et al examined the efficacy of fluconazole for provoked vulvodynia. After a six month regimen of 150 mg per week there was no significant difference between the treatment group (15% success rate) and the placebo group (30% success rate).²²¹

Other oral medications not studied for vulvodynia

Diazepam

Intravaginal diazepam suppositories as an adjunctive treatment for high-tone pelvic floor dysfunction and sexual pain have given significant clinical improvement in one report.²²²  5-10 mg ia prescribed in a compounded vaginal suppository nightly for 30 days, with titration of dosing frequency at successive visits as pelvic floor physical therapy progresses. It is possible to insert a diazepam 10 mg tablet vaginally although some women have difficulty retaining the tablet. There are reports of a blue green discoloration of vaginal secretions after local diazepam. Vaginal valium can be less sedating than oral valium; if sedation occurs, the dose can be lowered to 2.5 mg. The potential for habituation with vaginal diazepam is unknown; patients need to understand that habituation may occur.A double blind randomized placebo controlled trial evaluated the effectiveness of vaginal diazepam in addition to transcutaneous electrical nerve stimulation (TENS) in the treatment of vestibulodynia. Decreased visual analogue pain scores were not statistically significant. Vestibular nerve fiber current perception threshold for all of the nerve fibers increased after the treatment, but this increase was significant in the diazepam group only for the values at a 5-Hz stimulation (C fibers) with a change of 47.8% vs 26.9% (p<0.05).

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs have not been adequately studied for vulvodynia; they are widely anecdotally reported to be ineffective. In one study of provoked vulvodynia, the observed low expression of cyclooxygenase 2(COX 2) and inducible nitric oxide synthetase (iNOS)²²³ suggests that NSAIDs would not be helpful.

Corticosteroids

Corticosteroids have strong anti-inflammatory effects by reducing the production of interleukin-beta, which researchers have found elevated in the hymeneal tissue of women with vulvodynia.²²⁴ Smaller and likely underpowered RCT’s using high potency topical steroids have shown negligible effects.^{225 226} Some  success has been noted in case reports and series using combined local subcutaneous infiltration of lidocaine and a steroid (methylprednisolone or beta methadone) to the vestibule.^{227 228}  In a large RCT, researchers randomly assigned women to topical hydrocortisone 1% twice daily or group CBT of 12 sessions. Both groups showed a significant improvement in pain and sexual functioning post-treatment, but effects were larger among the women in the CBT group. ²²⁹ Again, more randomized study on both topical and injectable steroids is needed.

Opioids

Opioids have shown consistent efficacy in neuropathic pain,²³⁰ and patients with nociceptive pain syndromes may also require opioid therapy if they do not respond to nonopioid analgesics, or if their pain is severe at the outset.²³¹ Use of opioids has not been well studied for vulvodynia. We have found that it is helpful to use over the short-term an opioid, such as acetaminophen with codeine, 625/30 every 4-6 hours while awaiting the efficacy of a longer acting medication, such as one of the tricyclic antidepressants. Proactive management of constipation is essential.

Tramadol

Tramadol (Ultram™) inhibits the reuptake of serotonin and norepinephrine and may provide analgesia through this mechanism. Systematic reviews found that tramadol was effective for relief of neuropathic pain²³² and pain in patients with fibromyalgia.²³³

The dose is 50-100 mg by mouth every 4-6 hours not to exceed 400 mg/day.

Tramadol has similar side effects of other weak opioids, although the incidence of gastric upset may be higher. Seizures are an additional risk, particularly in patients who take antidepressants, neuroleptics, or other drugs that decrease the seizure threshold. Tramadol has been associated with increased risk for suicide,²³⁴ and must be used with caution in patients who have emotional disturbance, suicidal ideation or attempts in the past, or are addiction-prone. Although tramadol is not scheduled as a controlled substance, dependence has been reported.²³⁵

Non-pharmacologic treatment for vulvodynia

Tetrahydrocannabinol

Female mice were sensitized to the hapten dinitrofluorobenzene (DNFB) dissolved in saline on their flanks, and subsequently challenged with the same hapten or saline vehicle alone for ten consecutive days either on labial skin or in the vaginal canal. The study evaluated tactile ano-genital sensitivity, and tissue inflammation at serial timepoints. DNFB-challenged mice developed significant, persistent tactile sensitivity. Allergic sites showed mast cell accumulation, infiltration of resident memory CD8⁺CD103⁺ T cells, early, localized increases in eosinophils and neutrophils, and sustained elevation of serum Immunoglobulin E (IgE). Therapeutic intra-vaginal administration of Δ⁹-tetrahydrocannabinol (THC) reduced mast cell accumulation and tactile sensitivity. Mast cell-targeted therapeutic strategies may therefore provide new ways to manage and treat vulvar pain potentially instigated by repeated allergenic exposures.²³⁶

Laser

Most of the available studies are limited by their design: lack of a control group, lack of randomization, inadequate, short-term follow up, small series. Most studies are industry sponsored. Histological  evidence is commonly reported as proof of tissue regeneration after LASER treatment. However, the histological changes noted can also be consistent with reparative changes after a thermal injury rather than necessarily representing regeneration or restoration of function.²³⁷ Recently published studies regarding the efficacy of LASER therapy in the treatment of vulvodynia are few in number and suggest limited efficacy. A retrospective study indicated less pain with sexual intercourse among  24 of 37 women, but 35% of the patients required vestibulectomy to control pain symptoms.²³⁸ A 2016 study of 70 women who underwent fractional micro-ablative CO2 LASER for vestibular pain and vestibulodynia or menopausal symptoms secondary to GSM/VVA showed statistically significant improvement in dyspareunia and pain scores, but there was no statistically difference in outcomes between the study groups.²³⁹ A 2017 double blind, randomized,  placebo controlled study of 34 women treated with low-level LASER therapy versus placebo showed clinical pain improvement in 78% of the LASER group as well as 44% in the placebo group. But Q-tip test, intercourse pain on the Visual Analog Scale, and tampon tests before and after treatment, severity of discomfort in daily activities and/or in daily pain intensity did not show a difference between groups.²⁴⁰ The ICS/ISSVD Best Practice Consensus Document of 2019 therefore does not recommend LASER for routine treatment of vulvodynia unless part of a well-designed clinical trial or with special arrangements for clinical governance, consent and audit.²⁴¹

Injections and blocks

Botulinum Toxin

One treatment for pain with possible effects on central sensitization is botulinum toxin (BoNT).²⁴².

In muscle, BoNT blocks acetylcholine release from presynaptic neurons at the nicotinic neuromuscular junction. The mechanism in pain likely relates to its ability to similarly block the release of pain-associated pro-inflammatory neurochemicals, including glutamate, CGRP, and substance P. Thus, when applied to chronic pelvic pain, BoNT may not only target peripheral sources of pain such as pelvic floor muscle spasm, but may also reduce peripheral and central sensitization.²⁴³

BoNT injections have been used for both provoked and spontaneous pain, injected into the vestibule and/or pelvic floor muscles to reduce hypertonicity. Initially a few case reports and small series suggested that the modality was beneficial.

Doubt arose from a randomized, double blinded, placebo controlled study injection of 20 I.E. Botox in the bulbospongiosis muscles of women diagnosed with vestibulodynia that did not reduce pain, improve sexual functioning, or impact the quality of life compared to placebo, evaluated at 3 and 6 months follow up. In a systematic review, there was fair evidence of a lack of efficacy for botulium toxin injections for localized provoked vulvodynia.²⁴⁴ For generalized vulvodynia there was insufficient evidence in a case report,²⁴⁵ and a study of a small number of women.²⁴⁶

Higher doses of the toxin appear to have brought greater success. In a randomized, double-blinded, placebo-controlled trial, injection of botulinum toxin type A 80 units into the pelvic floor muscles has been shown to be more effective than placebo at reducing pain and pelvic floor pressure in women with chronic pain and muscle spasm.²⁴⁷  A retrospective cohort study of all women with intralevator Botox injection (100-300 Units) at a Boston hospital from 2005 through 2010  demonstrated effectiveness in 79.3% of women with refractory myofascial pelvic pain with few, self-limiting adverse effects.²⁴⁸

The growing body of literature on the use of BoNT to treat vaginismus, vulvodynia and chronic pelvic pain consists largely of case reports, case series, and uncontrolled trials. A recent review of BoNT literature by investigators at the National Institute of Health was performed for methodological details to aid the development of a consistent procedure for clinical treatment. The reports are overwhelmingly positive.²⁴⁹

Steroid/lidocaine

Success with injections of steroid/lidocaine has been reported in localized, provoked vulvodynia.^{252 253}

Interferon

Interferon injections, both intralesional and intramuscular, appeared hopeful for localized provoked vulvodynia in the past,^{256 257} but are not in widespread use at present. A recent review suggests that Interferon treatment may be considered for women with vulvodynia and histologic findings suggestive of HPV infection, if other treatments have failed.²⁵⁸

Serial nerve blocks

An observational study including 27 women reported that serial nerve blocks (combination of caudal, epidural, pudendal, and local infiltration) significantly improved vestibular pain. Follow-up, however, was limited to 8 to 12 weeks.²⁵⁹ Pudendal and spinal nerve blocks have been used for diagnosis and management of generalized vulvodynia. Guided image blocks are preferred to support or rule out the diagnosis since failure of traditionally performed pudendal nerve block in labor may be due to operator error and not necessarily the absence of PN. To date, evidence is limited to small studies.

Since the autonomic sympathetic nervous system conveys nociceptive messages from viscera to the brain, interventions with the sympathetic system are being used for perineal pain management. Ganglion impar blocks, steroid injection around the terminal branch of the sympathetic chain in the presacral space, have been performed with good results for generalized vulvodynia.²⁶⁰ Hypogastric plexus and L2 lumbar sympathetic blocks are being investigated.

Pudendal nerve blocks are both diagnostic and therapeutic. Good evidence is lacking, but the block has been shown of value in small studies. In a group of 26 women a series of five CT-guided blocks at the ischial spine over a five month period yielded a 62% reduction in pain.²⁶¹ In a prospective study of 55 patients, 87% had good to excellent outcomes.²⁶² In a recent study by Fannuci et al.,²⁶³ 27 patients with pudendal neuralgia underwent CT guided pudendal nerve blocks. At 1-year follow-up, 92% showed continued clinical improvement.

For spontaneous pain unresponsive to medical management, evaluation for entrapment of the pudendal nerve may be pursued.²⁶⁴ The nerve may be tested for delays in conduction; if abnormality is present, successful relief of pain by pudendal block may lead to surgery to release entrapment. There are four described approaches to surgical decompression of the pudendal nerve. All surgical methods involve neurolysis to eliminate the possible source of compression. The trans-gluteal approach is currently the most common and successful approach for pudendal neurolysis.²⁶⁵ This procedure was originally described by Professor Roger Robert from Centre Hospitalier Universitaire in Nantes, France. In a sequential, randomized, controlled trial, 71.4% of the surgery group compared with 13.3% of the non-surgery group had improved at 12 months.²⁶⁶

Transcutaneous electrical nerve stimulation

Transcutaneous electrical nerve stimulation (TENS) is a well known nonpharmacologic, noninvasive treatment to relieve pain from multiple etiologies. TENS reduces pain through both peripheral and central mechanisms. Centrally, sites in the spinal cord and brainstem that utilize opioid, serotonin, and muscarnic receptors are activated by TENS. In peripheral sites, TENS application produces analgesia though opioid and alpha-2 noradrenergic receptors.²⁶⁷ Weekly intravaginal TENS sessions combined with pelvic floor rehabilitation and biofeedback brought improvement in vulvar pain in 75.8% of all cases.²⁶⁸ In a double-arm randomized placebo-controlled trial there was improvement in all main outcome measures in 40 women with vestibulodynia.²⁶⁹

Subcutaneous stimulation treatment

Peripheral nerve stimulation (PNS) has been successful in the treatment of mononeuropathies. The target site of pain is stimulated transcutaneously, percutaneously or via permanent neuromodultaing implant. Electrodes in the painful area stimulate the affected region and have been helpful for pain conditions such as post-herpetic neuralgia, intractable hip pain, and occipital neuralgia. Clinical success using subcutaneous vulvar stimulation with an 80% improvement in pain has been reported. ²⁷⁰ The mechanism of action is augmented central pain processing in vulvodynia patients as compared to healthy, pain-free controls, based on sensitization of the peripheral and central nervous system.

Radiofrequency (RF) treatment of sacral nerve roots and ganglion impar

An RF lesion will stop nociceptive (A-delta and C fibers) input into the central nervous system without having a destructive effect on motor or sensory (a delta) fibers. Pulsed RF uses relatively high voltage applied near a neural tissue in short pulses, which avoids a significant rise in temperature, and should be more selective for C fiber denervations, so as to decrease the chances for sensory or motor deficit.²⁷¹ Pulsed radio frequency (PRF) may interfere with normal cell function at the dorsal root ganglion that is induced through changes in myelin and changes in the intracellular axonal components of the pain afferents.²⁷²

Use of radio frequency on the ganglion impar has proved effective in visceral pain syndromes and/or sympathetic pain syndromes of the perineal region. Placement of a radio frequency electrode through the sacrococcygeal ligament has been effective in relieving perianal pain when the latter is sympathetically mediated via the ganglion impar.²⁷³

Treatment with sacral nerve roots and spinal cord neuromodulation

The FDA supports sacral neuromodulation for disorders of the urinary tract, including idiopathic overactive bladder, urinary incontinence, or chronic nonobstructive urinary retention; pelvic floor disorders have not been approved as an indication for this technique.²⁷⁴ A small study of five women with chronic pelvic pain treated with lumbar and sacral nerve root stimulation was adequate to control paresthesias in all patients and pain scores declined from 9 to 2.²⁷⁵ In another single case, sacral neuromodulation for treatment of vestibulodynia resulted in excellent patient satisfaction after two years of follow up.²⁷⁶ In another isolated case of a 21 year old female with intractable vulvar pain without response to vulvar vestibulectomy with Bartholin gland excision, researchers concluded that spinal cord stimulation may offer a new treatment for women with intractable neuropathic vulvar pain.²⁷⁷

Mindfulness and mindfulness meditation focus on becoming aware of all incoming thoughts and feelings, and accepting them without attaching or reacting to them.²⁷⁸ Mindfulness improves conscious attention and awareness, fosters well being, decreases pain and catastrophizing, and increases positive emotional states. ²⁷⁹ Mindfulness-based cognitive therapy utilizes the traditional cognitive therapy methods with the addition of mindfulness and mindfulness meditation. In a matter of weeks, novice meditators have been shown to develop brain changes associated with memory learning, emotion regulation, self-awareness, cognitive flexibility in support of perspective taking, and less stress. In long term meditators brain scans show even more of these positive effects. ²⁸⁰ With encouragement of women to exercise, help others, engage in enjoyable social interaction or a pleasant activity, play, laugh, learn something useful and practice mindfulness or a meaningful spiritual activity, clinicians will be promoting positive emotions to help decrease pain.

The premise of cognitive behavioral therapy is that changing maladaptive thinking leads to change in affect and in behavior.²⁸¹ For provoked vulvodynia, the treatment aims to decrease pain, reduce fear of pain, and reestablish satisfying sexual function.²⁸²

A 2001 randomized study that looked at CBT, randomized participants to group CBT (CBGT), biofeedback, or vestibulectomy. Women in the three treatment groups reported significant improvement in their pain (47% – 70% for vestibulectomy, 19%-35% for biofeedback, and 21% – 38% for CBGT). While the surgery was significantly more successful than the other two treatments for pain reduction, all three treatments yielded equally significant psychosexual functioning improvements. There was a significantly lower attrition rate for the CBGT group compared with surgery. CBGT participants were more satisfied with their treatment than those in the biofeedback group.²⁸³

A 2006 study of CBT for provoked vulvodynia was a prospective evaluation of CBGT efficacy in a large sample. The researchers reported a significant decrease in dyspareunia as well as a significant improvement in sexual satisfaction and perceived pain control.²⁸⁴

A 2005 Cochrane Review confirmed modest positive effects from CBT on pain in various clinical conditions compared to other psychological treatments.²⁸⁵ CBT can increase a woman’s sense of control over her pain. It encourages positive expectations about pain severity that are powerful reducers of pain intensity.²⁸⁶

In a 2015 Swedish study, 60 women suffering from provoked vestibulodynia were treated over a 10-week period with a combination of mucosal desensitization and pelvic floor exercises and CBT. There was a statistically significant increase in sexual fantasies, increased sexual pleasure, excitement, and vaginal lubrication after completion of treatment. Pain occurred less often, resulting in significantly less avoidance of sexual intercourse, increased frequency of self-stimulation and intercourse.²⁸⁷

A 2019 randomized controlled study set out to compare the effectiveness of mindfulness-based group cognitive behavior therapy (M-gCBT) versus education support group therapy for the pain and distress associated with provoked localized vulvodynia. Participants were randomly allocated to either M-gCBT or education support. Average tampon test pain scores decreased compared with baseline at every time point in both study groups. Equally important are the sexual outcomes. Almost all outcome measures improved after the 8-week M-gCBT course with sustained improvement at the 6-month follow-up. When compared with education support, M-gCBT exhibited significantly improved Female Sexual Function Index and Generalized Anxiety Disorder  scores immediately after intervention and these were sustained at 3 and 6 months. The Beck Depression Index in the M-gCBT group showed significantly greater improvement compared with education support at 6 months. Finally, because both groups showed improvement in all sexual outcome domains, it implies that either treatment may be beneficial. ²⁸⁸

CBT has not been studied for generalized vulvodynia but appears to be a promising, readily available modality without negative side effects in need of further study.

Other resources include:

The Benson-Henry Institute for Mind Body Medicine at Massachusetts General Hospital:

https://bensonhenryinstitute.org/
Mindfulness-Based Stress Reduction (MBSR) worldwide program directory
http://w3.umassmed.edu/MBSR/public/searchmember/aspx

Physical therapy to the pelvic floor

Pelvic floor physical therapy and biofeedback are modalities that are used frequently by those who treat women with vulvodynia. These are discussed in (Annotation L The pelvic floor.)

Adjunctive and alternative therapy

There are few studies that have looked at adjunctive or alternative therapies. The ones that have been done so far lack controls and randomization.

Hypnotherapy

A single case study²⁸⁹ and another study of eight women²⁹⁰ showed significant reduction of pain.

Hypoallergenic vulvar hygiene

A prospective evaluation of a hypoallergenic vulvar hygiene program of 14 specific practices targeted for provoked vulvodynia. Twenty percent of the participants had a complete response; 57% had a partial response.²⁹¹  A limitation was the inability to identify the impact of each of the strategies.

Acupuncture

A prospective study of the efficacy of acupuncture showed that participants reported significant improvement in quality of life but their pain response was not reported.²⁹²

Surgical intervention

Vestibulectomy (modified perineoplasty) is often recommended for women who have failed medical management of their provoked pain. Patients with spontaneous pain or pain lateral to Hart’s line are not considered appropriate candidates. Preoperative pain mapping in the operating room prior to induction of anesthesia is essential to outline the areas of pain.

The surgery consists of a U-shaped incision in the vestibule starting at the level of Skene’s glands or lower, carried down laterally along Hart’s line medially to the perianal skin and extended superiorly to the level of the mapped pain on the opposite side. The vestibule is dissected medially to include the hymenal remnants, and the specimen is excised. The margins between Hart’s line and the medial paraurethral and vaginal tissue are re-approximated with sutures. Some surgeons mobilize the margin of the vaginal mucosa and bring the tissue inferiorly (vaginal advancement) to suture in place over the excised area from 5-7 o’ clock. Vestibulectomy technique may also utilize the Woodruff and Parmley perineoplasty,²⁹³ or a modified vestibulectomy developed by Goetsch, limiting the excision to the posterior fourchette.²⁹⁴

Disparate results have been reported for vestibulectomy.²⁹⁵ Most authors recognize that the absence of randomization leads to bias.²⁹⁶ Reported levels of satisfaction with the surgery span a wide range: 21%²⁹⁷. A retrospective questionnaire was administered to 37 women who had undergone vestibulectomy. Eight women reported being completely pain free after surgery, whereas the remaining 29 women reported various levels of pain and decreased sexual function. the authors concluded that vestibulectomy provides a suboptimal response to surgical treatment. The next value in the range was 40%²⁹⁸;52%²⁹⁹;56%³⁰⁰;66.7%³⁰¹. These researchers conducted a review and concluded that surgery seems to be effective, although the specific procedure employed is of little importance. When these authors compared long-term well-being after surgery vs. conservative treatment, they found that dyspareunia decreased significantly in both groups; however, some with severe vestibulitis could benefit from vestibulectomy, although results are similar to conservative treatment: visual analogue scale (VAS) reductions of 66.7% in the surgery group and 78.1% in the conservative treatment group. A higher value is reported by Bergeron, et al: 68%.³⁰². These researchers compared vestibulectomy with biofeedback and cognitive behavioral therapy. Surgery yielded pain reduction two times higher (68%) than the behavioral treatments. No behavioral treatment worsened the pain, but in the surgical group, 9% had worsened pain by the time of follow-up: ³⁰³78%³⁰⁴ 83%³⁰⁵;91%³⁰⁶

The surgical treatment studies have methodological deficiencies. Besides the limitations of no controls or comparison groups in the majority of the studies, only the two cited above are randomized. Other weaknesses include a lack of a double-blind evaluation process, lack of descriptive information about the women in the sample, and no depiction of how pain was measured at baseline. Pain was evaluated subjectively without standardized tools. Follow up time periods vary between studies with no initial definition of successful outcome. Surgical technique varies, although there is currently insufficient evidence to support that any one specific vestibulectomy surgical technique is superior to another.³⁰⁷ Surgery is reported to have a placebo effect of 35%,³⁰⁸ and we know that a 40%-50% placebo effect is documented in randomized controlled trials of nonsurgical interventions for provoked vulvodynia.^{309 310 311}

Despite the methodological weaknesses, surgery has continued to be cited in the literature as a sound treatment option, albeit not a first line intervention.³¹² The most recent review of the literature indicates that despite a fair amount of evidence, as above, of the effects of vesitibulectomy, such evidence is not enough to accurately determine the degree of effectiveness of these treatments, as studies were performed without placebo control groups.³¹³

A study from 1999 to 2005 of two groups treated with conservative management or posterior vestibulectomy compared long–term well-being of women who needed surgery or did not need surgery in the treatment of severe vulvar vestibulitis syndrome. Long–term sexual well-being did not differ between the two groups. Overall, 89% of the women in both groups were satisfied with the treatment. Women with atopic skin problems were less likely to need surgery (odds ratio 0.2; 95% confidence interval 0.1-0.7).³¹⁴

It is important to recognize that with the 2015 classification of pain there are many possible sources of pain to be considered.  We are frequently able to determine a known cause of vulvar pain, especially early desquamative inflammatory vaginitis, that appears to sensitize the vestibule, and the multiple causes of high tone pelvic floor dysfunction. The need to perform vestibulectomy continues to decline for us.