Alessandra Graziottin1, 2 and Filippo Murina3
(1)
Center of Gynecology and Medical Sexology, H. San Raffaele Resnati, Milan, Italy
(2)
Graziottin Foundation for the cure and care of pain in women, Italy
(3)
Department of Vulvar Disease V. Buzzi Hospital Obstetrics and Gynecological Clinic, University of Milan, Milan, Italy
Abstract
Vulvodynia is a complex syndrome of vulvar pain with sexual dysfunction and psychological disability. Its etiology remains elusive but several lines of investigation support a neuropathic etiopathogenesis for the disease. The manifestation of vulvodynia may be caused by more than one factor and may vary in each patient.
Vulvodynia is a complex syndrome of vulvar pain with sexual dysfunction and psychological disability. Its etiology remains elusive but several lines of investigation support a neuropathic etiopathogenesis for the disease. The manifestation of vulvodynia may be caused by more than one factor and may vary in each patient.
Vulvar pain is an unpleasant and emotionally arousing sensory experience that invades womens’ consciousness, and chronic pain is maladaptive and evokes human suffering. Chronic (also known as persistent) pain is defined when it last for at least 3 months. However, the mechanisms involved are more important than the duration of the pain. Chronic pain is associated with changes in the central nervous system (CNS), which may maintain the perception of pain in the absence of acute injury.
Recent evidence from human studies has significantly expanded the understanding of pain perception and has demonstrated that a complex series of spinal, midbrain, and cortical structures are involved in pain perception.
How Complex Is Vulvar Pain Transmission into the Central Nervous System?
Pain transmission from the periphery to the higher brain centers via the spinal cord is not a simple, passive process involving exclusive pathways (Fig. 6.1). The relationship between a stimulus causing pain and the way it is perceived by an individual is dramatically affected by circuitry within the spinal cord and the brain. The sensation of pain is modulated as it is transmitted upwards from the periphery to the cortex. It is modulated at a segmental level and by descending control from higher centers, with the main neurotransmitters involved being serotonin, norepinephrine (noradrenaline) and the endogenous opioids.
Fig. 6.1
Schematic representation of pain pathways
· The peripheral nociceptors are simple bare-ending nerve fibers that are wide-spread in the superficial layers of the skin. Nociceptors are classified as: Aδ, which are small-diameter, lightly myelinated, and C-fibres, which are not myelinated. Neurons originating at the nociceptors pass into the peripheral nerves and enter the spinal cord at the dermatomal level ascribed by their insertion. Innervation to the vulva is via the pudendal nerve which originates from the S2-4 nerve roots and the ilioinguinal and genitofemoral nerves, arising from L1-2. The latter two nerves are predominantly sensory, but the pudendal nerve contains motor, sensory, and sympathetic fibers which supply the complex autonomic reflexes of the pelvic organs. The vagina itself is relatively insensitive to pain, while the vulva and particularly the vulvar vestibule have a high level of free nerve endings.
· Spinal cord. Following spinal-cord integration of afferent inputs there are neurons (second-order neurons) that transmit the information to the higher centers via ascending pathways. The classical ascending pathway ascribed to pain is the spinothalamic one; other pathways relevant in pain modulation include the spinomesencephalic, spinoreticular and dorsal column pathways.
· Cerebral cortex. Cortical pain perception can be roughly divided into a lateral, somatosensory system involved in the discrimination of pain location and intensity, and a medial system which mediates the anticipatory, fearful, affective quality of pain through limbic structures. In broad terms, pain has elements that are sensory and localizing, and other elements that are involved in memory, cognition and affect.
· Descending pathways. Some of the spinothalamic fibers project to the periaqueductal grey (PAG) and hypothalamus and then to the dorsal horn of the spinal cord. The PAG is an area of the brain that is rich in opioid receptors and is thus involved in the endogenous opioid system. The descending pathways are, therefore, inhibitory at the dorsal horn, reducing ascending nociceptive inputs.
What Happens in Neuropathic Pain and why Can We Consider Vulvodynia as a Neuropathic Pain Syndrome?
Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Neuropathic pain results from damage to the nervous system anywhere along the neuraxis: peripheral nervous system, spinal or supraspinal nervous system, or brain. Clinically, neuropathic pain is expressed by two abnormal sensory processes manifest as hyperalgesia and/or allodynia. Hyperalgesia is defined as an increased response to a stimulus that is normally painful, while allodynia as pain due to a stimulus that is not normally painful.
Vulvodynia patients exhibit these two basilar elements: hyperalgesia and/or allodynia.
Box 1
Glossary
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• Allodynia: Pain perception evoked by a stimulus that under normal conditions evokes non-painful sensations |
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• Central sensitization: A phenotypic change in CNS pathways that leads to the augmentation of the processing of nociceptive stimuli |
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• Hyperalgesia: Enhanced pain perception evoked by a stimulus that under normal conditions evokes painful sensations |
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• Nociception: Pain and pain behaviors evoked by the application of a brief noxious stimulus |
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• Nociceptors: Primary nerve fibers that respond to tissue injury or stimuli that are capable of evoking tissue injury |
The steps involved in generation of neuropathic pain (Fig. 6.2) are:
· Peripheral change after nerve damage. Injury to free nerve endings induces structural and functional changes in both injured and uninjured parts of the nerve. These changes increase ectopic and spontaneous firing after nerve damage, furthermore ‘cross-talk’ from neighboring nerves (damaged or not) can augment this effect. Regeneration of axon terminals after nerve damage may enhance cross-talk, although the degree of sprouting does not correlate with the severity of pain behaviors. Hyperalgesia and allodynia are the symptomatic expressions of these phenomena. Inflammation has been suggested to be pivotal to the development of peripheral sensitization. Nerve grow factor (NGF) appear to be a key molecule in the orchestration of peripheral inflammation. NGF is released from many cells after tissue injury and has several pro-inflammatory roles. Indeed, NGF has significant action on the expression of other inflammatory mediators (interleukin-1β and tumor necrosis factor, etc.) and it is also capable of direct and indirect sensitization of nociceptors. Inflammation-driven release of cytokines from immune cells provokes hyperalgesia through stimulation and production of other pro-inflammatory agents.
Mast cells are the main source of inflammatory mediators. These peripheral cell types are located in the dermis, adjacent to blood vessels, nerve endings and glandular ducts, and have a cytoplasm filled with spherical granules. Mast cell granules contain many factors implicated in neurogenic inflammation, such as NGF, tumor necrosis factor (TNF), proteases and cytokines.
Physical, chemical and mechanical stimuli activate local mast cells, causing degranulation and secretion of mediators that have been found to sensitize and induce the proliferation of C-afferent nerve fibers. These nerve fibers release inflammatory mediators, including NGF, which increase the proliferation and degranulation of mast cells, causing hyperesthesia, and enhance the inflammatory response. Mast cells show particular complexity in relation to the inflammatory response, and their density in inflamed tissue changes over time. In tissue where there is an acute inflammatory response, the concentration of mast cells is high. As the inflammation becomes more chronic the number of mast cells decreases and there is a parallel increase in neuronal proliferation. At this stage of the inflammatory process neuropathic symptoms became prominent, but mast cell reactivation can occur at any time, with an exacerbation of symptoms or acceleration of neurogenic inflammatory processes.
· Central mechanism. The dorsal horn is now known to play a key role in the modulation of pain (Fig. 6.3) and the development of chronic pain states. Pain is perceived only if this electrical activity reaches the brain and, hence, any modulation of alteration within the dorsal horn can have profound effects on pain sensation. Laminas IV and V of the dorsal horn contain a peculiar type of neuron called wide dynamic range (WDR). Repetitive stimulation by C-fibers cause some WDR cells in the dorsal horn to augment their response. Thus, for a given input stimulus, the output is enhanced; this process is referred to as ‘wind up’. Wind up is a part of a process termed ‘central sensitization’. Cortical functioning has localizing, emotional and memory components. Descending modulatory control is bidirectional in nature. These descending control systems link the brain cortex to the dorsal horn, acting either directly on primary afferents or indirectly via inhibitory and excitatory interneurones.
The phenomena described above lead to central sensitization, a pivotal aspect of neuropathic pain. Central sensitization involves an increase in the receptive fields of a nociceptor, an increase in the magnitude and duration of its response to a noxious stimulus and a reduction in the threshold required to stimulate nociceptors.
Fig. 6.2
Mast cell activation
Fig. 6.3
Structure of the dorsal horn
What happens in vestibulodynia/vulvodynia patients?
Vestibular proliferation of C-afferent receptors (ten-fold increase in the density of nerve endings) and a significant number of activated mast cells (assessed by measuring mast cell degranulation levels) have been reported in vestibulodynia patients.
Biopsies from the area around the ductal openings of Bartholin glands, the most sensitive vestibular area in most vestibulodynia patients, have shown significantly more intraepithelial free nerve endings than in healthy control subjects.
It is possible that the epithelium of the vulvar vestibule expresses an abnormal response to ‘trigger’ inflammatory events such as infection, trauma and repeated exposure to an irritant or allergen, with a subsequent increase in the number of activated mast cells. Their activation is associated with the discharge of various mediators from the granules, such as NGF, tryptase and bradykinin. The various mediators secreted by mast cells are known to sensitize C-nerve fibers and induce their proliferation. Neurogenic inflammation is the most appropriate definition of this series of events (Fig. 6.4).
Fig. 6.4
Neurogenic inflammation
Recent lines of evidence highlight a potential genetic predisposition to chronic inflammation among vestibulodynia-afflicted women. These genetic polymorphisms lead to a reduced capacity to terminate and to an exaggerated inflammatory response.
The findings of multiple case-control studies of women with provoked vestibulodynia suggest that they experience more frequent vaginal infections. A history of recurrent candidiasis infections is one of the most consistently reported findings associated with the onset of vestibolodynia. A reduced capacity to control Candida albicans action due to a polymorphism in the gene coding for mannose-binding lectin, an innate immune system antimicrobial protein, has been reported and this polymorphism has also been associated with vestibulodynia.
It has also been demonstrated that women with vulvodynia more frequently react to patch tests for Candida albicans, and it was postulated that exposure to Candida albicans at low concentrations may involve neurotransmitters that have been shown to influence contact hypersensitivity and are present in abundance in the vulvar vestibule.
It is clear that recurrent Candida albicans infection may play a central role in the triggering of vestibulodynia.
Conversely, others have found no evidence for active tissue inflammation in vestibulodynia patients, as assessed by inflammatory markers (cyclo-oxygenase-2 and inducible nitric oxide synthase) that are usually up-regulated during the inflammatory process.
In vulvodynia patients there is no active inflammation, rather we find a neurogenic inflammation, particularly in vestibulodynia patients, where prolonged or severe infectious, thermal or chemical irritation causes excessive local responses (mast cell activation).
It is our opinion that the inflammatory character of vestibulitis can be reconsidered, thus justifying its nosological name (see Chapter 2).
The morphological findings of nerve-ending proliferation has not been demonstrated for generalized vulvodynia, but new elements have been identified in this subtype of disease where there is a scarcity of research on the pathophysiology.
As with patients with neuropathic pain, women with generalized vulvodynia exhibit hyperalgesia and/or allodynia, which can be considered a functional effect corresponding to neural hyperplasia. Our recent study indicates that the current perception threshold (CPT) values were lower in women affected by vulvodynia than those in controls, suggesting a hypersensitivity (Fig. 6.5).
Fig. 6.5
Results of current perception threshold (CPT) measures in 3 selected stimulation frequencies (2,000-, 250-, and 5-Hz) in healthy volunteers (control) and in women with a diagnosis of generalized vulvodynia (patients). Each stimulation frequency reflects the pattern of sensory function of the 3 major sensory fiber types (Aβ, Aδ, and C). Women with vulvodynia showed mean CPT values significantly lower than the controls did at each frequency (p < .01) (Murina F et al., 2010)
The CPT measures provide objective and quantitative determinations of the sensory nerve conduction and nerve functional integrity, and it uses an electrical stimulus selective for the large and small myelinated and unmyelinated fibers that are involved in the transmission of painless and painful sensation.
Each of the three major sensory fiber types has a characteristic neurophysiological profile, sensory function, sensation evoked by electrical stimulation, and conduction block susceptibility. Because findings of enhanced pain perception are typical of neuropathic pain syndromes, our results add strength to a neuropathic hypothesis for pain also in generalized vulvodynia (see Fig. 6.5).
Triggers
It is always difficult to find a trigger for inflammatory events in generalized vulvodynia. Women with generalized vulvodynia experience symptoms anywhere within the distribution of the pudendal nerve (Fig. 6.6).
Fig. 6.6
Vulvar pudendal nerve distribution
The pudendal nerve is an extrapelvic nerve; it quickly exits the pelvis, wraps around the ischial rectal fossa, enters the pudendal canal, and provides innervations to the external genitalia, the urethral sphincter, the anal sphincter, and the vagina. The branch that innervates the vulva and vestibule is very superficial, while the branch that innervates the clitoris is deeper. Thus, there is the possibility of repeated micro-trauma to the vulvar branch, for example during bicycling and horseback riding, which could lead to neurogenic inflammation.
Several lines of investigation support the elements of central sensitization in vulvodynia patients.
Particularly, some authors have demonstrated that vestibulodynia patients perceive light and moderate touch to the vulvar vestibule more intensely than do control women. The increase in perception is reflected in more significantly activated neural areas than in control women. In addition, it has been shown that vestibulodynia in young women is associated with increased gray matter density in pain modulatory and stress-related brain regions. It has been speculated that increased gray matter density could be caused by microglial proliferation, maybe due to excess excitatory neural activity.
Box 2
Central Sensitization
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• Increased pressure sensitivity in both the vulva and peripheral body regions |
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• Increased pain intensity and unpleasantness in response to tenderpoint examination in non-genital sites |
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• Higher levels of brain activity in primary and secondary somatosensory cortices during application of pressure to the posterior vestibule |
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• Lower pain pressure thresholds to noxious cold stimulation, suggesting a systemic hypersensitivity |
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• Higher gray matter density in pain modulatory and stress-related areas |
Modified from Vulvodynia: Integrating Current Knowledge into Clinical Practice, by the National Vulvodynia Association, 2010 (www.nva.org), with permission
This description of vulvodynia is supported by a good deal of evidence, but there are some open questions regarding its etiology, including:
What Is the Relationship Between Vestibulodynia and Generalized Vulvodynia?
Some clinicians think that provoked vestibulodynia and generalized vulvodynia may be variations in severity of the same disorder. The etiopathological process has been suggested to first result in the localized pain of vestibulodynia and then progress to the chronic, generalized vulvar pain; instead, our experience suggests that the two conditions may be two distinct disorders. The two subtypes of vulvodynia can be clearly distinguished by some characteristics such as age, symptoms and triggering inflammatory factors. Nevertheless, individuals may have aspects of both vestibulodynia and generalized vulvodynia, with overlapping symptoms.
There are many problems with this hypothesis, such as patients who have prolonged vestibulodynia without ever developing generalized vulvodynia, and those, whose condition starts with generalized vulvar pain but never develop introital dyspareunia. The common element is that both of these conditions represent a form of vulvar reflex-sympathetic neuropathic pain with sensitization of nociceptive C fibers, so that touch sensation is replaced with an experience of pain.
In our opinion a different subtype of vestibulodynia exists that is distinguishable by certain characteristics such as trigger factors, age, pelvic floor dysfunction and comorbidities, rather than two diseases classified upon the vulvar symptoms localization and characteristics of pain (provoked or unprovoked).
What Is the Role of Pelvic Floor Dysfunction?
Electromyographic studies of the pelvic floor in women with unprovoked pain have shown differences compared with asymptomatic patients. Pelvic floor hypertonic dysfunction is found in 80% to 90% of patients with vulvodynia. A relevant topic to be investigated is whether vulvodynia reflects pelvic floor dysfunction with trigger points of pain, or whether it is a form of referred pain, or a result of dysfunctional nerve fibers in the pelvis.
In vulvodynia, there is obviously nerve involvement in pain. The leading opinion indicates that vulvar pain can produce spasm of the levator ani muscle, and pelvic floor hypertonicity contributes to self-maintenance of pain. In summary, the levator ani muscles are innervated by the levator ani nerve, while no evidence of innervation by the pudendal nerve can be found. The levator ani motor neurons are diffusely distributed in the sacral ventral horn, while the pudendal motor neurons are concentrated in Onuf ’s nucleus (a group of neurons located in the ventral part of laminae IX of the anterior horn; see Fig. 6.3). However, there is a great deal of overlap between the dendrites of levator ani motor neurons and pudendal motor neurons, and both nerves contain primary afferent fibers that project into the sacral spinal cord. Thus, there is great potential for interaction between the sensory and motor nerve fibers that control the levator ani muscle, the vulva, and the vestibule. It is not important what starts the process (muscle or nerve) but it is important how alteration of the pelvic muscles is responsible for the severity of symptoms.
Indeed, “the weight of the muscle” may be different between patients with vulvodynia and this is the only important target of the treatment program.
What Is the Role of Hormonal Alteration as a Potential Cause of Vulvodynia?
Some studies have concentrated on the effects of estrogen on peripheral nervous system pathways, emphasizing those that pertain to pain. A review of the literature reveals a somewhat common idea that there is a relationship between estrogen and sensation, and that a decrease in threshold occurs with increased estrogen levels, such as during the menstrual cycle, pregnancy, and estrogen replacement. This may explain a change in symptoms during the menstrual cycle; in fact some vulvodynia patients can have an exacerbation of symptoms during the premenstrual period. Furthermore, the vulvar vestibule is embryologically analogous to the urogenital gland in males. These glands have a high density of androgen receptors, which implies that adequate testosterone levels are essential for the maintenance of healthy vestibular tissue.
It is unclear whether oral contraceptives (OC) play a role in the development of vulvodynia. Some clinicians propose that the use of OCs, particularly at an early age, down-regulates estrogen receptors in the vulvovaginal tissue, causing an altered morphological pattern in the vulvar vestibule; the epithelium can appear thin and fragile and a decrease of lubrication can be observed. OC use has been associated with a 7-fold increase in the risk of developing vestibulodynia. The risk is higher with current, long-term or early use, and with use of OCs of high progestogenic potency and low estrogenic and androgenic potency. Until a causal effect is demonstrated, however, women should not be discouraged from using OCs, but should be made aware of vestibulodynia.
In a notable study published in 2004, Bernard Harlow showed that women taking oral contraception who reported vestibulodynia were much more likely to have difficulty or be unable to use tampons for menstrual protection. This would suggest the presence of hyperactivity of the levator ani prior to first coitus (lifelong or primary) which may be associated with moderate vaginismus. Muscular contraction mechanically restricts the vaginal opening, predisposing the woman to pain upon initial penetration, reflex inhibition of lubrication with consequent vaginal dryness, and microabrasions of the mucosa of the vaginal opening, thus favouring chronic inflammation, the proliferation of pain nerve fibers and a further increase in the defensive contraction of the levator ani.
TIP: The examination of a patient taking oral contraception who reports “vaginal dryness and/or painful coitus” should therefore consider:
1.
whether the levator ani is hypertonic. If so, teach the patient to relax the muscle with various techniques, including stretching, physiotherapy and electromyographic biofeedback;
2.
the vaginal pH. If higher than 5, this is a sign of little oestrogen impregnation and an indication to increase the oestrogen level of the pill, commence local oestrogen therapy or at least to use vaginal acidifiers to improve the composition of the vaginal ecosystem.
Otherwise there is the risk of blaming the contraceptive pill, which merely acts as a litmus test indicating other problems relating to muscles, the vaginal ecosystem and/or fear of coitus which deserve to be treated in an appropriate manner.
How Relevant Are Psychosexual Factors in Vulvodynia Patients?
Psychological morbidity is significantly higher in women with vulvodynia compared with asymptomatic women. Many studies demonstrate high degrees of anxiety, depressive symptoms, somatization disorders and hypochondriacal symptoms in vulvodynia patients.
While some propose that the syndrome has a purely psychogenic origin, the leading opinion suggests that sexual dysfunction and psychological distress are the consequence rather than the cause of vulvodynia. However, this concept is still under debate.
The anterior cingulate brain cortex (ACC) contributes to the control of the state of conscious arousal and attention based on prefrontal cortical innervations. Anxiety dependent pain exacerbation is also mediated by other limbic structures, such as the hippocampus. A history of abuse or trauma is common in chronic pelvic pain patients, and this is also mediated by limbic dysfunction, particularly of the ACC, hippocampus, and amygdala.
It has been observed that vulvodynia patients have higher rates of sexual abuse, including threatened sex, forced intercourse, lifetime sexual victimization and severe child sexual abuse, an association that appears to hold true for other vulvodynia comorbidities such as irritable bowel syndrome (IBS) and interstitial cystitis (IC). Although there is a degree of association, several studies have refuted the notion that prior sexual and/or physical abuse is a predisposing factor for vulvodynia.
Regardless of the sequence of events, physical and psychological factors produce a continuum with multiple dimensions of pain. Studies show lower frequency of intercourse, decrease in desire and increased difficulty achieving orgasm, and many patients with vulvodynia who do have intercourse do so out of a sense of obligation rather than desire.
In conclusion, it is still impossible to say whether psychosexual factors are involved in the development or maintenance of vestibulodynia, or whether they are the consequence of an undiagnosed, persistent and debilitating pain. Pain modulation by psychological factors is one of the most complex problems; in vulvodynia patients, psycho-neurobiological vulnerability plays a relevant role and the experience of pain varies depending on the patient’s psychological state.
Why Is There a Frequent Association Between Vulvodynia and Other Chronic Pain Conditions?
Vulvodynia is frequently associated with bladder pain syndrome (BPS/IC), IC, a urological condition of urinary urge, frequency and bladder spasms, IBS, and fibromyalgia, a condition encompassing pervasive muscle pain and sleep disorder. All these conditions share a common denominator: a chronic inflammation, which is the major contributor of chronic pain and related symptoms. Histological data (from the colonic mucosa in IBS, from the bladder wall in BPS, from the vulvar vestibule in vulvovestibulitis, and from deep endometriosis in the pelvis and/or abdomen), show three common findings in the examined specimens: significant increase of mast cells; significant increase of degranulated mast cell, suggestive of a very active inflammatory state; significant increase of mast cells close to pain nerve fibers. These findings support the close relationship between chronic inflammation and chronic pain and suggest that the hyperproduction of inflammatory molecules (interleuchines 1 and 8, tumor necrosis factor alpha etc.) may contribute to local and systemic comorbidities. New data suggest that depression may be caused/worsened by the flooding of the brain, by the inflammatory molecule produced by the hyperactive mast cells typical of chronic inflammation. The frequent overlap of irritable bowel syndrome, interstitial cystitis, vulvodynia, and other chronic pelvic pain disorders may be indicative of aberrant neuronal interactions or reflexes, such that the irritation of one organ leads to co-sensitization of others. With continued irritation, neurotrophic factors produced by both smooth muscles and sensory neurons may influence neurite outgrowth and axonal sprouting, which could lead to motor and sensory changes in target organs.