Ezio Vincenti, Alessandra Graziottin
Vulvar vestibulitis syndrome and vulvodynia, which clinically appear with symptoms typical of neuropathic pain, such as allo- dynia and hyperalgesia, represent the main cause of sexual pain disorders during the fertile age (see Chapters 12.1-12.4 and 12.6 of this book). Because of the severe vestibular pain when attempting vaginal entry, intercourse is increasingly avoided. When the disease is in an advanced state, pain is suffered spontaneously, almost while sitting or moving. In some chronic cases, pain/discomfort may radiate from the vulva to the perineum and into the groin and thigh.
If both current medical treatment and noninvasive anthalgic therapy fail to control pain, repeated anesthetic neural blockades may be the definitive solution. The rationale for this new approach is based on the results obtained in other chronic neuropathic pain diseases and from pathophysiologic data recently acquired in the specific vulvar field. In fact, recent histologic and biochemical findings from vestibular tissues of patients affected by vulvar vestibulitis syndrome or vulvo- dynia1-3 have stimulated a new and more effective therapy for cases defined as intractable.
Anesthetic block of the impar ganglion (and specific somatic nerves) and ancillary anthalgic systemic supportive therapy have modified the general approach to the treatment of these patients, who previously were scheduled for ablative surgery of the vestibulus, i.e., vestibulectomy. Pathophysiologic considerations are necessary to elucidate the rational basis of this therapeutic approach.
Acute injury to the vulvar vestibule by bacterial, fungal, or viral infection, chemical irritants, or coital rubbing without lubrication and a defensively contracted elevator ani further reducing the vaginal entrance, as well as iatrogenic procedures, may cause acute pain triggered by the mucosal damage that lasts from several days to a few weeks. This causes an inflammatory response with a typical nociceptive pain, which may be resolved by the correct symptomatic and etiologic approach.4 When the tissue damage is persistent because the predisposing and/or precipitating damaging factors remain undiagnosed and/or unaddressed, a chronic inflammation of variable intensity is maintained. The mast cells, key mediators of it, become upregu- lated. Their production of nerve growth factors promotes nerve pain fiber proliferation, which correlates with hyperalgesia, and superficially causes allodynia, the perceptive shift from tactile to burning pain.1-4 This explains why pain may become persistent despite treatment. When nerves work in abnormally, signaling pain without apparent peripheral damage, the term “neuropathic pain” may be used. This pain also describes the process by which the neurons involved in pain transmission are converted from a state of normal sensitivity to one in which they are hypersensitive.
Initially, pain is due only to peripheral mechanisms, but later central mechanisms are progressively recruited. The pathophysiology of peripheral neuropathic pain is therefore based on both abnormal peripheral inputs and abnormal central processing.1-5 Peripheral mechanisms include nociceptor sensitization, spontaneous activation of primary afferent fibers ectopi- cally firing from the site of the lesion, and so-called neurogenic inflammation.
The last is characterized by the release of algogenic substances, which may move backward along the sensory nerves and/or be released by the upregulated mast cells through neurogenic activation of their degranulation. A close interaction between mast cells and pain nerve fibers, with reciprocal potentiation, seems to be a key feature of peripheral neuropathic pain. As far as the central mechanisms are concerned, a “wind-up” phenomenon occurs due to the progressive increase of cellular firing after repeated identical electrical stimuli.6 Moreover, spinal and supraspinal propagation of abnormal local changes caused by peripheral nervous lesion is responsible for aberrant central elaboration. In the biochemical field, excitatory amino acids and N-methyl-D-aspartate receptors play a crucial role in the genesis of chronic neuropathic pain.6
The dorsal horn of the spinal cord seems to be extremely important in the initiation and maintenance of neuropathic pain. Recently, Tsuda et al.7 have demonstrated that activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia of the dorsal horn contributes to pain hypersensitivity to innocuous stimuli (tactile allodynia) after peripheral nerve injury. In fact, intrathecal administration of a specific p38 mitogen-activated protein kinase inhibitor (SB203580) suppresses the development of the nerve injury-induced tactile allodynia. Other investigations8 show that galectin-1 (one of the endogenous galactoside-binding lectins, involved in a variety of functions, such as neurite outgrowth, synaptic connectivity, cell proliferation, and apoptosis) increases in the dorsal horn at 1-2 weeks after axotomy. Furthermore, intrathecal administration of antirecombinant human galectin-1 antibody partially but significantly attenuates the upregulation of substance P receptor in the spinal dorsal horn and the mechanical hypersensitivity induced by the peripheral nerve injury. These data suggest that endogenous galectin-1 may support neuropathic pain after the peripheral nerve injury, at least partly, by increasing substance P receptor in the dorsal horn.
Tissue injury of almost any kind, but especially peripheral or central neural tissue injury, can lead to long-lasting spinal and supraspinal reorganization that includes the forebrain.9 These forebrain changes may be adaptive and facilitate functional recovery, or they may be maladaptive, preventing or prolonging the painful condition.9,10 In an experimental model of heat allodynia, functional brain imaging showed that: (a) the forebrain activity during heat allodynia is different from that during normal heat pain; (b) during heat allodynia, specific cortical areas, specifically the dorsolateral prefrontal cortex, can attenuate specific components of the pain experience, such as affect, by reducing the functional connectivity of subcortical pathways. The forebrain of patients with chronic neuropathic pain may undergo pathologically induced changes that can impair clinical response to all forms of treatment.
Therefore, both peripheral and central mechanisms are involved in maintaining intractable neuropathic pain arising from the vulvovaginal area. The new strategy of treatment is based on the destructuring of acquired anatomic and functional neuronal modifications during chronic pain, while respecting the anatomic integrity of the vestibular tissue. The ablative approach, which aims at removal of the inflamed vestibular mucosa, was proposed at a time when the pathophysiology of burning pain was not understood. Addressing the etiologic diversity of vulvar vestibulitis syndrome by multimodal treat- ment,4 and specifically curing pain by appropriate anthalgic strategies, both peripheral and central, takes into account the current pathophysiologic understanding and the need for maintenance of anatomic integrity for a better sexual outcome.
The transition from nociceptive to neuropathic pain is key in vulvar vestibulitis syndrome/vulvodynia, as it underlies the shift from a sexual pain disorder, where intercourse elicits and provokes pain, to a progressively pure pain disorder that is spontaneously self-maintained despite the avoidance of any further coital intimacy. Some women with chronic vulvar vestibulitis syndrome/vulvodynia report distress from noncoital activity such as kissing or hugging their partner, dreaming, or watching an erotic movie, as even mild genital arousal (without direct contact) with the resultant vasocongestion immediately elicits a provocation of the genital pain.
From the nosologic point of view, neuropathic pain arising from vulvar vestibulitis syndrome and vulvodynia may be associated clinically with a complex regional pain syndrome6 early recognized as reflex sympathetic dystrophy, an increasingly diagnosed entity. Spontaneous burning pain worsening over time, tenderness, and increasing psychologic involvement with a catastrophizing coping attitude are the main complaints of patients suffering from vulvar vestibulitis syndrome and vulvo- dynia. The pathophysiology of physical symptoms is related to the microscopic findings of proliferation of pain fibers, which are superficial within the vestibular tissue.
Persistent vulvar allodynia and hyperalgesia that cause dys- pareunia lead to the avoidance of intercourse.4 In the absence of appropriate treatment, pain tends to worsen and widen in the perineal and bladder area. Patients with vulvar vestibulitis syndrome have increased innervation and/or sensitization of thermoreceptors and nociceptors in their vestibular mucosa. In patients with vulvar vestibulitis syndrome, Bohm-Starke et al.2 found the presence of allodynia to mechanical testing with von Frey filaments (14.3 ±3.1 mN in the symptomatic posterior area compared with 158 ± 33.5 mN in healthy subjects), as well as to the pain threshold to heat (38.6±0.6°C in patients and 43.8 ± 0.8 in controls). In addition, the pain threshold to cold was 21.6 ± 1.2°C in patients, whereas cooling down to 6°C was usually not painful in controls.
The classic definition of vulvar vestibulitis syndrome by Friedrich11 concerning the constellation of symptoms and findings involved, and limited to the vulvar vestibule, consists of (a) severe pain on vestibular touch to attempted vaginal entry, (b) tenderness to pressure localized within the vulvar vestibule, and (c) physical findings confined to vulvar erythema of various degrees. This defiinition seems to be consistently valid only for (a) and (b), since many patients suffering from neuropathic pain may present an apparently normal mucosa without current signs of erythema. Indeed, there may be a more appropriate definition of vulvodynia for these cases. According to Bergeron et al.,12 erythema does not appear to be a useful diagnostic criterion; in addition, no active inflammation was seen in biopsies obtained from the vestibular mucosa by analysing cyclooxygenase 2 and inducible nitric oxide synthase by the indirect immunohistochemistry method.
A basic therapeutic approach to vulvar vestibulitis syndrome/vulvodynia is mandatory.4 Hygienic and behavioral recommendations should be given in order to avoid chronic irritation and maceration of the fragile tissues, and improve perineal care. Prevention of yeast infection recurrence should be maintained with antimycotic oral treatment. Food intake should be qualitatively controlled as well, to reduce vestibular irritation during micturition, and to reduce recurrence of Candida. Relaxation of the pelvic floor should be obtained through self-massage, physiotherapy, and/or electromyographic feedback.4,13 In fact, treatment of underlying causes of organic and psychologic etiologic specific factors in particular must be done before effective anthalgic therapy. The authors suggested specific guidelines for management of neuropathic pain due to vulvar vestibulitis syndrome/vulvodynia (Table 12.5.1).14
As a rule, patients with intractable (concerning the conventional therapy) neuropathic pain from vulvar vestibulitis syndrome/vulvodynia need the second (invasive, nonsurgical) stage of treatment. The pathophysiologic basis of this approach should be sought in the histologic alterations of vestibular innervation, which appears intraepithelially increased in the mucosa of vulvar vestibulitis syndrome/vulvodynia patients. If chronic aggressive factors can transform normal mucosa into an altered histologic picture (Fig. 12.5.1), a correct, ad hoc pathophysiologic treatment with periodic anesthetic blocks can restore the normal innervation. The persistent efficacy of nerve block therapy may be explained as follows. The anesthetic block of specific afferent fibers (especially neurovegetative) from an area involved in neuropathic transmission might induce a progressive self-reduction (neuroplasticity) of the hyperplastic peripheral nervous arborization in the intraepithelial field, with a parallel reduction of the neurogenically induced degranulation of the upregulated mast cells. In fact, even a transient anesthetic deafferentation repeated monthly should be sufficient to modify an altered (excessive) supply of nervous endings, functionally producing allodynia and hyperalgesia as a result of reduced pain threshold. Therefore, we have employed monthly anesthetic nerve blocks of the impar ganglion,4,14 which is the last ganglion of the sympathetic chain and has the task of transmitting sympathetic information to and from the perineal area. Regarding somatic deafferentation, repeated anesthetic blocks of some regional somatic nerves may complete the recovery of status quo ante.
As far as materials and methods are concerned, every session of blocks is currently composed of anesthetic blocks of sacral, pudendal (through perineal pathway), and ilioinguinal nerves, and finally of the impar ganglion (under the guidance of a finger rectally introduced) (Fig. 12.5.2), which is the main target. Plain 0.25% bupivacaine is used in a total volume of no more than 30 ml per session, delivered by 30-90-mm, 23-gauge, disposable needles.
The correct use of these anesthetic blocks offers a dramatic improvement in clinical conditions by controlling burning pain immediately (onset time less than 2 min). After the first sessions of anesthetic blocks, the duration of pain relief is limited to a few hours or days. After 2-3 months, pain-free time becomes longer, up to a few weeks’ duration. Within about 6 months, more than 80% of patients affected by intractable pain from vulvar vestibulitis syndrome/vulvodynia obtain persistent pain relief, rating more than 93% in comparison with the preblock period (Table 12.5.2). Follow-up of cases reported here are longer than 6 months.
Figure 12.5.1. Schematic pictures of normal mucosa and mucosa of vulvar vestibulitis syndrome patients.
Table 12.5.1. Guidelines for nonsurgical management of neuropathic pain due to vulvar vestibulitis syndrome/vulvodynia. Stages of treatment (a multimodal, interdisciplinary treatment approach)
1. Conventional, noninvasive
b. Electromyographic biofeedback of pelvic floor musculature13
c. TNS (transcutaneous nerve stimulation)
2. Invasive, nonsurgical
a. Peripheral anesthetic blocks (impar ganglion; sacral, pudendal, and ilioinguinal nerves)14
b. Sacral nerves stimulation by implantable catheters15
Figure 12.5.2. Anesthetic block of ganglion impar. Reproduced from Vincenti and Graziottin14 with permission.
For additional comfort when pain relief by block therapy is still incomplete, gabapentin and tricyclic antidepressant (amitriptyline) drugs are used. Dosage is adjusted by the principle of minimum effective dose, or of the dose allowing acceptable minor side effects. Parallel treatment of the predisposing, precipitating, and maintaining factors contributing to chronic agonist stimuli upregulating the mast-cell degranulation is recommended.
Table 12.5.2. Casistics and results of anthalgic treatment with anesthetic nervous blocks in patients suffering from intractable pain caused by vulvar vestibulitis syndrome/vulvodynia (more than 6 months after completion of treatment)
Number of cases
age (years) (average, range)
Duration of time (years) (average, range)
of intractable pain before invasive therapy
Number of anthalgic sessions (median value, range)
Percentage of cases with complete recovery Pain before treatment (visual analog scale 0-100)
pain after treatment (visual analog scale 0-100)
When the neuropathic pain has disappeared, therapy should be initiated to (re)gain sexual pleasure and satisfactory intimacy with adequate genital arousal. The shift from pain to pleasure may require parallel biologic and psychologic treatment, addressing the issues of both the woman and the couple.4 The sexual prognosis is dependent upon the duration of sexual pain, the damage to the couple’s intimate relationship, and the efficacy of the support in addressing pre-existing, concomitant, and persisting sexual health issues, such as low libido, poor mental and genital arousal, and fear of re-experiencing pain.
Early and appropriate management of pain associated with vulvar vestibulitis syndrome/vulvodynia is key for both the effectiveness of the anthalgic treatment and the successful outcome of the sexologic therapy.4
Current noninvasive treatment may be useful in a number of patients, but the most severe cases need a more aggressive approach, such as anesthetic nerve blocks. Monthly repeated blocks with bupivacaine of the impar ganglion and of the sacral, pudendal, and ilioinguinal nerves, complemented by ancillary therapy with antidepressant and anticonvulsant (e.g., gabapentin) drugs, in many patients may progressively reduce the intensity of pain and its extension until complete recovery. This invasive but nonsurgical therapy seems to be the most effective treatment for women affected by severe neuropathic pain caused by vulvar vestibulitis syndrome/vulvodynia and resistant to current noninvasive therapy.
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