Pathophysiology of chronic pelvic and perineal pain in women

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A classic clinical observation in women presenting with chronic pelvic pain is the poor correlation between identifiable pathologic processes, the chronicity and severity of pain and the impact of symptoms on quality of life.

This is exemplified by endometriosis, a condition affecting women predominantly in the reproductive age group and characterized by the presence of endometrial glands and stroma outside the endome-trial cavity. The condition is thought to arise mainly by i mplantation of endometrial tissue following retrograde menstruation via the fallopian tubes [1]. It presents a clinical spectrum, with endometriotic deposits sometimes observed at laparoscopy in the absence of symptoms or tissue damage, through sub-fertility apparently associated with endometriosis but in the absence of pain, to chronic pain associated with disabling pain symptoms and often gross damage to the pelvic organs through abnormal invasion of endometriotic deposits into the pelvic tissues, neo-vascularization and adhesion formation. In a series of asymptomatic multiparous patients undergoing sterilization, the prevalence was 26/3384 (3.7%) [2]. There is a relationship between the depth of invasion of endometriosis and the intensity of pain symptoms,

Evidence-Based Chronic Pain Management. Edited by C. Stannard, E. Kalso and J. Ballantyne. © 2010 Blackwell Publishing.

established with some difficulty through small but detailed histopathologic studies [3]. In this study nerve fibers could usually be identified in specimens of deeply invading endometriosis. Pain was present in 17% of those with deposits invading <2 mm, 53% of those with 2- 4 mm deposits, 37% of those with 5-10 mm deposits and all six women with very deep deposits of >10 mm. No wholly reliable predictive set of criteria has emerged from studies of symptom profiles. Only the severity of dysmenorrhea was useful in predicting the diagnosis of endometriosis at laparos-copy [4].

Based on a study of uterine specimens removed at hysterectomy for endometriosis, other forms of chronic pelvic pain and for nonpain indications, Atwal et al. proposed a concept of reinnervation and microneuroma formation as a mechanism for uterine pain and tenderness, with these features being seen in specimens from patients with painful conditions but not in those from patients without pelvic pain [5]. The study did not proceed to characterize the neu-rotransmitter profile of the nerves which may have given further information about the sensory processes and pathways involved. The neurotransmitter expression of nerves growing into experimental implants in a rat model mimicking endometriosis did indicate the presence of both autonomic and sensory components [6].

Some of the above may be explained by the extent to which pathologic processes are associated with the release of inflammatory mediators, which again may reflect biologic variations in the response to tissue damage. Immune hypotheses have been proposed in relation to endometriosis, but there are no data to link specific patterns of host response with symptoms. Although mechanisms of visceral nociception have been clarified through animal experimental studies of the feline bladder [7], and processes such as activation of silent afferents following inflammation have been demonstrated, there is a dearth of evidence as to the place of such mechanisms in the pathophysiology of abnormal visceral sensation in women. Nevertheless, in the clinical setting, it is a frequent observation that chronic pain can develop following infection that has apparently resolved, which may point to processes such as the activation of silent afferents. Chlamydial infection, in particular, is often associated with tissue damage in the absence of acute symptoms and may account for visceral sensitization. Adhesions may form after inflammation due to sepsis, following surgery and may be associated with endometriosis. Innervation of adhesion tissue has been described [8]. However, any causal relationship with pain symptoms is unclear.

Vulvodynia is a chronic disorder in women, characterized by provoked or constant vulvar pain of varying intensity without obvious concomitant clinical pathology. Two subsets of vulvodynia are recognized: generalized and localized pain subtypes, the latter currently referred to as vestibulodynia or vestibulitis.

With regard to vulval or perineal pain, trauma is often suspected as a causal factor in the pathogen-esis, whether during childbirth or through injury to the pelvis. Again, such episodes may be coincidental. Nerve conduction studies to assess damage to the pudendal innervation have proved of marginal value in clinical practice. A syndrome of entrapment of the pudendal nerve in Alcock's canal has been described [9]. It is not clear whether neuropathic processes are involved in this proposed mechanism, what the impact of surgical intervention is on the conduction properties of afferent fibers and whether central sensitization is a feature of the clinical presentation.

Immune and inflammatory mediators have been considered in the pathogenesis of endome-triosis and have also received much attention in the case of vulval vestibulitis or vestibulodynia.

As with endometriosis, it is unclear whether the primary problem is inflammation or the associated nociceptive processes. Evidence for the latter is the observation in a functional MRI study of increased cerebral neuronal activity during painful vulval vestibular stimulation among patients with vulval vestibulitis syndrome compared with that seen among controls [10]. At the tissue level there is evidence for neuronal proliferation [11] but no excess of cyclo-oxygenase or inducible nitric oxide activity [12]. Previous causative hypotheses around human papillomavirus or herpes genitalis infection have been discounted in molecular studies of clinical biopsy specimens.

Pelvic muscle spasm may be a feature of chronic pelvic pain [13] and it is often difficult to establish whether this is the primary problem or is a natural response to the presence of pelvic tenderness arising from another condition such as endometriosis. Spasm of the levators certainly contributes to additional distressing symptoms such as urinary retention, constipation and dyspareunia.

A vascular pain mechanism, pelvic venous congestion, has been proposed as a cause of chronic pelvic pain and relevant endothelially mediated vascular pain mechanisms have been demonstrated in human studies. There are questions about the association between pain symptoms and particular radiologic or ultrasound appearances that have become somewhat more difficult to interpret with the advent of interest among interventional radiologists in embolization of "pelvic varices" [14].

Hormonal factors are important mediators of nociception in both animal and human experimental models. Variations of pain threshold and behavior were demonstrated in relation to sex hormone exposure in rats at different stages of the estrus cycle. Responses to distension of the uterus and vagina and pain behaviors overall showed heightened responsiveness during metestrus and diestrous compared to proestrus and estrus [15]. Meta-analysis of studies of women undergoing experimental exposure to different pain modalities at different stages of the menstrual cycle indicated an effect size of 0.40 for variation in pain sensitivity between the most and least sensitive phase [16].

Figure 13.1 Pain intensity among UK pain clinic patients with chronic pain (all causes) and women with chronic pelvic pain [19].


Figure 13.1 Pain intensity among UK pain clinic patients with chronic pain (all causes) and women with chronic pelvic pain [19].

As with chronic pain in general, genetic factors may give rise to susceptibility to pelvic pain. In clinical genetic epidemiologic studies, it is difficult to distinguish between genetic susceptibility to a condition such as endometriosis, that may give rise to pain, and susceptibility to pain per se. In an Australian cohort of female twins who were questioned on two occasions 8 years apart, the longitudinally stable variance attributable to genetic and environmental factors could be calculated. Whereas 39% of the variance in reported menstrual flow was accounted for by genetic factors, the corresponding figure for dysmenorrhea was 55%, and for functional limitation from menstrual symptoms was 77% [17]. Using the same twin cohort, the genetic contributions to endometriosis and somatic distress (as a proxy for nociception) were 38% and 15% respectively [18].

Once patients with chronic pelvic and vulval pain reach the stage of assessment in a pain clinic, it appears that the pattern of symptom impact is similar to that seen in other chronic painful conditions in terms of severity and lifestyle impact (Fig. 13.1). It remains a clinical challenge to individualize assessment and treatment either to focus on "specific" pathologies such as endometriosis or to emphasize pain management and understanding of the pathophysiology as discussed above. Best clinical practice suggests an approach that recognizes both dimensions.

Table 13.1 Classification of causes of chronic pelvic pain. Reproduced from Stones [20].

Inflammatory, infective

Chronic salpingitis Inflammatory, noninfective

Endometriosis Vulvodynia with dermatosis


Uterine retroversion Adhesions


Pelvic congestion Irritable bowel syndrome


Postsurgical Dysesthetic vulvodynia Vulval vestibulodynia


Pelvic floor myalgia

Abdominal and pelvic trigger points

Postural muscle strain

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