Chronic, nonmalignant pain syndromes of the perineal area have been well described in the medical literature dating back more than 100 years. However, the etiology of these focal pain syndromes is poorly understood. The patient who is experiencing pain in the perineal area is often embarrassed because these areas of the body are considered taboo in our society. These pain syndromes are frequently underreported and underrecognized.

Patients with these pain syndromes often have seen a variety of specialists in different subspecialties—including urologists, gynecologists, gastroenterologists, proctologists, and internists—and, despite an extensive evaluation, no specific etiology has been found in the majority of cases. Not surprisingly, many of these patients are frustrated because they have suffered from chronic pain for many years, but the disease has not been “given a name” and the pain is not controlled. It is important to recognize that these focal chronic pain syndromes of the perineal area do exist. The etiology of these pain syndromes is not known, and a specific secondary cause can be identified in a minority of patients only. Although these patients often are depressed, rarely are these pain syndromes the only manifestation of a psychiatric disease. Currently available treatment strategies are empirical only. Although complete cures are uncommon, effective treatment modalities exist to lessen the impact of pain and offer reasonable expectations of an improved functional status.

The intent of this chapter is to first give a brief overview of the current taxonomy of perineal pain in the context of pelvic pain and of the neurobiology of the perineal area and then to review the clinical characteristics and treatment strategies of the different perineal pain syndromes.

Similar to other areas in the health sciences, where multiple disciplines are involved, developing a uniform and comprehensive terminology that improves clinical communication and enhances research efforts into the etiology of perineal pain remains a challenge. The International Association for the Study of Pain (IASP) appointed a Task Force in Taxonomy early on to develop descriptions of pain syndromes and detailed pain definitions.¹ This pain terminology has been recently updated² by PUGO’s Classification Committee (PUGO is IASPs Special Interest Group for Urogenital and Pelvic Pain; PUGO has recently been renamed as the IASP Special Interest Group on Abdominal and Pelvic Pain) to reflect the emerging and multidisciplinary field of pelvic and urogenital pain. This taxonomy has been used in this chapter and reflects the multifactorial nature of perineal pain, requiring a multidisciplinary approach, as well as the multisystem aspects of the perineal pain complaint. To briefly review the concept of this 2012 taxonomy, perineal pain is presented under the umbrella term chronic pelvic pain. Chronic pelvic pain is chronic or persistent pain perceived in structures related to the pelvis of either men or women. Here, perceived indicates that the patient and clinician, to the best of their ability from the history, examination, and investigations (where appropriate) have localized the pain as being perceived in the specified anatomical pelvic area. Such pain is often associated with negative cognitive, behavioral, sexual, and emotional consequences, as well as with symptoms suggestive of lower urinary tract, sexual, bowel, pelvic floor, or gynecologic dysfunction. In the case of documented nociceptive pain that becomes chronic/persistent through time, pain must have been continuous or recurrent for at least 6 months. That is, it can be cyclical over a 6-month period, such as the cyclical pain of dysmenorrhea. Six months is arbitrary; however, 6 months was chosen because 3 months was not considered long enough if cyclical pain conditions are included. If nonacute and central sensitization pain mechanisms are well documented, then the pain may be regarded as chronic, irrespective of the time period.

Chronic pelvic pain may be subdivided into those conditions with well-defined classical pathology (such as infection or cancer) and those where no obvious pathology is found. For the purpose of this classification, the term specific disease-associated pelvic pain is proposed for the former and chronic pelvic pain syndrome for the latter. Chronic pelvic pain syndrome (CPPS) is the occurrence of chronic pelvic pain where there is no proven infection or other obvious local pathology that may account for the pain. CPPS is a subdivision of chronic pelvic pain (as described earlier). Pain perceived in the pelvis in CPPSs might be focused within a single organ, more than one pelvic organ, or even associated with systemic symptoms such as chronic fatigue syndrome, fibromyalgia, or Sjögren’s syndrome.

Many CPPSs are associated with a range of concurrent negative psychological, behavioral, and sexual consequences that must be described and assessed. Examples are depression, anxiety, fears about pain or its implications, unhelpful coping strategies, and distress in relationships—all of which need to be considered. Both anxiety and depression can be significant, important concomitants that are relevant with respect to pain, disability, and a poorer quality of life. Catastrophic interpretations of pain have been shown to be particularly salient variables, predicting patients’ reports of pain, disability, and poorer quality of life—over and above psychosocial variables such as depression or behavioral factors such as self-reported sexual dysfunction. It is suggested that CPPS symptoms sometimes create a sense of helplessness that can be reported as overwhelming in patients, which may be associated with the refractory nature of their symptoms. It is important to note that many of these biopsychosocial consequences are common to other persistent pain problems but may show varying degrees of salience for any one individual suffering from CPPS. In all patients with CPPS, these consequences must be clearly described as a part of the phenotype (where the term phenotype is used to indicate the observable characteristics of the syndrome).

It is well recognized that the end organ where the pain is perceived may not be the center of pain generation (e.g., the prostate in perineal pain in men). This classification is based upon the most effective accepted method of classifying and identifying different pains—that is, by site of presentation. It is argued that keeping the end organ name in the classification is inappropriate because, in most cases, there are multisystem causes and effects with the result that symptoms are perceived in multiple areas. This is a field where discussions are ongoing, and, despite there being strong arguments for both keeping and dispensing with an end organ classification, the IASP taxonomy has not taken the umbrella approach of referring to all pains perceived in the pelvis as being chronic pelvic pain syndrome.

The perineum is a highly specialized area of the body, responsible for carrying out a host of basic biologic functions, including defecation, micturition, copulation, and reproduction. The display of these diverse functions relies on precise nervous system control, coordinated with endocrine and other local control mechanisms. Compared with other areas of the body, there has been fairly little research on the neuroanatomy, neurophysiology, and neuropharmacology of the perineum.³ The complexity of the perineum in carrying out many different specialized functions has largely been considered to account for the slow progress in our understanding of the neurobiology of this area. The fact that these areas of the body often are considered taboo in our society also may account for the scarcity of research on this topic.

A detailed review of the neurobiology of the pelvic floor is provided by Burnett and Wesselmann.⁴ Briefly, the innervation of the perineum is served by both components of the autonomic nervous system—the sympathetic and parasympathetic divisions—as well as by the somatic nervous systems^5,6 (Figs. 45-1 and 45-2). Sensations from the pelvic floor are mainly conveyed via the sacral afferent parasympathetic system, with a far lesser afferent supply from afferents traveling with the thoracolumbar sympathetics.⁷ However, sensations of the testis and epididymis may predominantly involve thoracolumbar afferents.⁷ Somatic efferent and afferent innervation to the perineum originates from sacral spinal cord levels S2 to S4. Sacral nerve roots emerge from the spinal cord to form the sacral plexus, from which arises the pudendal nerve.⁸ The pudendal nerve also receives postganglionic axons from the caudal sympathetic chain ganglia.⁶ The pudendal nerve runs medial to the internal pudendal vessels along the lateral wall of the ischiorectal fossa dorsal to the sacrospinous ligament. First, a branch splits off to become the dorsal nerve of the penis (or clitoris); then, the remaining pudendal nerve fibers distribute a medial branch to the anal canal, dorsal branches to the urethral sphincter, and dorsolateral branches to the anterior perineal musculature. The posterior perineal musculature is supplied by nerves originating predominantly from sacral level S4. Branches of the S4–S5 nerve roots form the coccygeal plexus, distributing fibers to the perineal, perianal, and scrotal (labial) skin.⁹

Neuropeptide release appears to account for perineal sensations.⁷ Numerous peptides have been associated with afferent pathways of the pelvic floor, although a preponderance of evidence supports the roles of substance P and calcitonin gene–related peptide (CGRP) as the primary chemicals released from these sensory neurons.^10–12

VULVODYNIA (IASP CLASSIFICATION: VULVAR PAIN SYNDROME)

The term vulvodynia (Latin: vulva; Greek: –odynia, or pain) is a modern word for an age-old pain condition. Historically, vulvar pain cannot be separated from the earlier description of painful intercourse: dyspareunia.³ The first recorded reference to vulvar pain is embedded in the ancient Egyptian Ramesseum Papyrus more than 2000 years ago.¹³ Detailed descriptions of hyperesthesia of the vulva can be found in U.S. and European textbooks of gynecology from the last century.^14,15 Surprisingly, despite these early reports, the medical literature did not mention vulvar pain again until the early 1980s, when a new awareness of this chronic pain syndrome developed. In 1984, the International Society for the Study of Vulvar Disease (ISSVD) Task Force defined vulvodynia as chronic vulvar discomfort, characterized by the patient’s complaint of a burning and sometimes stinging sensation in the vulvar area.^16,17

The ISSVD stated that vulvodynia was a symptom rather than a diagnosis and that multiple etiologies might be possible. Subsequently, two subsets of vulvodynia were identified. One subgroup of patients complained about entrance dyspareunia (pain with tampon insertion and pain at vaginal penetration during sexual intercourse), rather than diffuse vulvar pain. The term vulvar vestibulitis was introduced for this subset of vulvodynia, and the following diagnostic criteria were established: (1) presence of severe pain on vestibular touch or attempted vaginal entry, (2) tenderness to pressure localized within the vulvar vestibule, and (3) physical findings confined to vestibular erythema of various degrees.¹⁸ The other main subgroup of patients with vulvodynia presented with generalized, spontaneous vulvar pain occurring in the absence of physical findings. The term dysesthetic (or essential) vulvodynia was suggested for this symptom complex. Clinically, two different groups of patients with vulvar vestibulitis have been described: Primary vulvar vestibulitis is defined as dyspareunia from the first attempt of sexual intercourse, whereas, in secondary vulvar vestibulitis, the dyspareunia appears after a period of pain-free sexual intercourse. It has been suggested that these two subgroups differ in etiological, clinical, and genetic variables.^19–23 Based on the concern that the suffix “-itis” in vulvar vestibulitis incorrectly implies an inflammatory etiology, the term vestibulodynia has been suggested.¹⁷ The most recent revision of the ISSVD of the terminology of vulvodynia was published in 2004.¹⁷ This classification suggests categorizing a generalized and a localized (vestibulodynia, clitorodynia, hemivulvodynia, etc.) form of vulvodynia and to differentiate subgroups within those two categories based on the observation of whether the vulvar pain is provoked, unprovoked, or mixed (provoked and unprovoked). Vulvodynia has a significant impact on patient’s psychological well-being and quality of life. Because of the location of the pain complaint, this pain condition has a significant effect on the patient’s sexual functioning. The Diagnosis and Statistical Manual of Mental Disorders-V suggests a single diagnostic entity called genito-pelvic pain/penetration disorder, which includes vulvodynia in the context of sexual pain disorders.²⁴

Community studies suggest that vulvar pain is common, but the prevalence rates vary widely from 3% to 18%.^25–29 A survey of sexual dysfunction, analyzing data from the National Health and Social Life Survey, reported that 16% of women between the ages of 18 and 59 years living in households throughout the United States experience pain during sex.³⁰ When these data were analyzed by age group, the highest number of women reporting pain during sex was in the age group of 18 to 29 years old. The location and etiology of pain was not analyzed in this study. Goetsch³¹ reported that 15% of all patients seen in her general gynecologic private practice fulfilled the definition of vulvar vestibulitis—a major subgroup of vulvodynia. It is important to point out that these patients had not come for a gynecologic evaluation because of vulvar pain but for a routine gynecologic checkup. Fifty percent of these patients had always experienced entry dyspareunia and pain with inserting tampons, and most of these had experienced pain since their teenage years. Epidemiological studies have confirmed that localized provoked vulvodynia is the most common vulvodynia subtype in premenopausal women.^25,26 Initial reports postulated that vulvodynia affects primarily women of Caucasian origin;^24,31 however, a survey in the United States of ethnically diverse women showed that Hispanic women were 80% more likely to experience chronic vulvar pain than were white and African American women.²⁶ A small study done in Ghana in 2005 revealed a prevalence rate of 20% in an all-black population.³² Vulvodynia affects women of all age groups. The incident of symptom onset is highest between ages 18 and 25, decreases through age 44, and then remains fairly constant.²⁶ Several widely divergent estimates have been postulated for the lifetime cumulative incidence of vulvar pain syndrome, ranging between 200,000 and 14 million women in the United States.²⁶

The etiology of vulvodynia is considered multifactorial. Systemic factors that facilitate abnormal inflammatory processes have been considered. It has been hypothesized that a subgroup of women experience vulvodynia of an inflammatory origin, yet the existence of such a subgroup has not been confirmed or rejected by clinical phenotyping efforts. Foster and Hasday found elevated tissue levels of interleukin I-ß (IL-1) and tumor necrosis factor alpha in vulvar tissue of patients with vulvodynia, but these proinflammatory mediators were actually at higher levels in the surrounding vulvar tissue than in the area of inflammation, confirming the clinical finding of a wider area of involvement beyond the area of erythema.³³ However, these results were not supported in a subsequent study by Eva and colleagues.³⁴ There is increasing evidence of genetic polymorphisms that are found more often in women with localized provoked vulvodynia, indicating that, in some women, the over- or underexpression of certain proinflammatory cytokines could underlie abnormal physiological mechanisms driving vulvar pain.³⁵ However, equivocal findings of occasional redness and inflammatory infiltrate in vulvar biopsy tissue of women with provoked vulvar pain have called this inflammatory hypothesis into question.³⁶

A possible etiological correlation between oral contraceptives (OCs) and provoked localized vulvodynia has been investigated in epidemiologic studies. In a clinic-based study from 2002, the results showed an increased relative risk of vulvar vestibulitis for users compared to nonusers.³⁷ These findings were, however, not confirmed by a population-based case-control study from 2008.³⁸ More data are urgently needed, and it has been recommended by European researchers to continue to prescribe the pill when it is needed, but both users and prescribers should be aware of side effects such as dryness, soreness, and pain;³⁹ however, no practice guidelines have been established.

Women with vulvodynia have lower touch detection and mechanical pain thresholds in the genital area compared to age-matched controls,⁴⁰ as well as heightened pain sensitivity at nongenital body sites,^40–42 indicating that vulvar pain may not simply be a local sensory phenomenon but that central pain modulatory mechanisms might be involved. Notably, some evidence suggests symptomatic overlap between vulvodynia and systemic pain disorders such as fibromyalgia.⁴³ MRI studies of the brain indicated that women with vulvodynia exhibit an augmentation of genital sensory processing that is similar to that observed for a variety of syndromes causing hypersensitivity, including fibromyalgia, irritable bowel syndrome, and neuropathic pain.⁴⁴

As in other pelvic pain syndromes, increased prevalence of comorbid psychopathology has been reported in women with vulvodynia,³ including higher rates of depression and anxiety. These findings might be considered either a cause or a consequence for different women. Personality characteristics in women with provoked vulvodynia include higher levels of trait anxiety, shyness, hysterical personality, perfectionism, reward dependency, low self-esteem, fear of negative evaluation, and harm avoidance, as compared to healthy female controls. Although women with vulvodynia, not surprisingly, report negative feelings about sexual contact with their partner, their relationship satisfaction regarding nonsexual aspects did not differ from controls.

Vulvodynia is a diagnosis of exclusion and is established largely through history and clinical examination.^3,45 On physical examination, patients with vulvodynia usually present with no visible abnormalities. Other causes of burning and irritation must be ruled out, including genital infections (candidiasis, human papillomavirus, herpes simplex virus, bacterial vaginosis), vulvar dermatoses, vulvar dysplasia, and urogenital atrophy. Local agents applied to the vulvar region can cause irritant reactions, which resolve after discontinuation of the irritant agent. Depending on the location of the pain, a diagnosis of generalized or localized vulvar dysesthesia is made. In patients with localized vulvar pain, pain can easily be elicited or exacerbated by a simple “Q-tip test,” where touching the dysesthetic area with a moist cotton swab results in sharp, burning pain. The natural history of vulvodynia over a woman’s life span is not well known. Approximately half of the patients with clinical symptoms of vulvar vestibulitis eventually seem to experience spontaneous remission.⁴⁶ Because the pathophysiologic mechanisms of vulvodynia are not yet known, targeted therapy is not available at present. Treatment approaches are empirical only. Multiple treatments have been used for vulvodynia, including vulvar care measures; topical, oral, and injectable medications, which have been used for other chronic pain conditions; biofeedback; physical therapy; low oxalate diet and calcium citrate supplements; surgery (perineoplasty and pudendal nerve release); implantable sacral nerve stimulation; and acupuncture, nitroglycerin, hypnotherapy, and botulinum toxin injections. Haefner and colleagues⁴⁷ reviewed the literature and provided guidelines based on expert opinion regarding the treatment of vulvodynia. A recent trial assessing the efficacy of oral desipramine and topical lidocaine, as monotherapy or in combination, failed to reduce vulvodynia pain more than placebo.⁴⁸ A randomized comparison of vaginal biofeedback, group cognitive behavioral therapy, and vestibulectomy found similar treatment outcomes for all modalities.⁴⁹

In summary, vulvodynia (vulvar pain syndrome) is a recognized disease entity, and an emerging body of literature is reporting on several different etiologic factors, attesting to the multifactorial aspects of this disease.⁵⁰ For the treating physician, it is important to realize that many women with vulvodynia are in their reproductive ages and previously had satisfying sexual relationships. In contrast to many other chronic pain syndromes, vulvodynia may only interfere to a moderate extent with the daily activities of a woman, but the disease usually interferes 100% with her sexual life. To confirm the diagnosis of vulvodynia (vulvar pain syndrome)—excluding secondary causes such as dermatitis or gynecologic infections—and to design a treatment plan, a multidisciplinary approach involving collaborations of gynecologists, dermatologists, neurologists, pain specialists, psychologists, psychiatrists, and sexologists is necessary.

IASP CLASSIFICATION (CLITORAL PAIN SYNDROME)

In contrast to the large body of literature that has emerged over the past 30 years on vulvodynia, few reports exist on clitoral pain. In the most recent revision of the ISSVD of the terminology of vulvodynia (vulvar pain syndrome),¹⁷ clitoral pain has been considered within the category of localized vulvodynia as clitorodynia, similar to other localized forms of vulvodynia such as vestibulodynia, hemivulvodynia, and the like. In clinical practice, clitoral pain occasionally is also seen in women presenting with generalized vulvodynia if the pain is extending throughout the whole perineum, and the ongoing pain (often a burning, stinging sensation) is usually exacerbated by mechanical stimuli such as tight clothing and sexual contact. Chronic pain is reported as one of the complications of female circumcision.⁵¹ This procedure involves excision of the clitoris and the labia minora and is still performed on young females in many parts of the world.^52–54 As mobility is increasing, some of these women have moved to Western countries; for example, it is estimated that 2000 young women living in the United Kingdom undergo this ritual per year.⁵³ Few of these women seem to seek medical attention, and the incidence of chronic pain in this group is not known. Reconstructive surgery after female genital mutilation has been reported to result in improvement of pain.⁵¹

URETHRAL PAIN SYNDROME AND SPECIFIC, DISEASE-ASSOCIATED URETHRAL PAIN

Many women present to the urologist, gynecologist, or family physician with painful micturition without evidence of organic disease. The urine culture is negative by standard techniques. Gallagher and colleagues⁵⁵ in 1965 coined the term urethral syndrome to describe this problem. Both the European Association for Urology and the International Association for Pain use the term urethral pain syndrome.^2,56 It has been estimated that urethral pain syndrome accounts for as many as 5 million medical office visits a year in the United States.⁵⁷ This syndrome is defined as a disease entity characterized by urinary urgency, frequency, dysuria, and, at times, suprapubic and back pain and urinary hesitance in the absence of objective urologic findings. Urethral pain syndrome typically occurs in women during their reproductive years, but it has also been reported in children and men.^58,59 In contrast to other chronic perineal syndromes involving nonmalignant pain, the rates of spontaneous remission are very high in this patient population.^60,61

Several different theories have been proposed to explain the etiology of urethral pain syndrome, most, however, with little supporting evidence. It has been suggested that symptoms are caused by urethral obstruction and, thus, are surgically treatable.^62,63 It is important to note that rarely is there evidence to support an anatomically obstructive etiology. Although surgical procedures aimed at relieving a urethral obstruction claim excellent results, it must be cautioned that long-term follow-up rarely is provided. These procedures involve some risk of incontinence and are of uncertain and usually temporary efficacy.^64,65 Urinary hesitance, which often is reported by patients with urethral syndrome, might be the result of spasms of the external urethral sphincter, rather than an anatomic obstruction. Several studies reported a staccato or prolonged flow phase during uroflowmetry and increased external sphincter tone detected on urethral pressure profilometry in patients with urethral syndrome.⁵⁸ However, these urodynamic findings may also be produced voluntarily in a neurologically intact person and are, therefore, difficult to interpret.⁶⁶ To date, an inflammatory or infectious etiology of the urethral syndrome has not been supported,⁶⁶ and controlled studies using molecular techniques to assess for infection are necessary to further clarify whether an occult infection is maintaining the chronic pain syndrome.

A thorough diagnostic evaluation is very important because the symptoms of urethral syndrome are indistinguishable from those caused by urinary infections, tumors, stones, interstitial cystitis/bladder pain syndrome, and many other urologic diseases. Urethral syndrome is a diagnosis of exclusion. The urologic evaluation includes urine analysis, culture, and cytology. Radiographic studies, urodynamic studies, and cystoscopy are indicated in selected patients.⁶⁶ Systemic diseases affecting the innervation of the urogenital area, including multiple sclerosis, collagen diseases, and diabetes mellitus, have to be included in the differential diagnosis. In female patients, a gynecologic examination is necessary to rule out symptoms that may be secondary to a gynecologic cause. As in other chronic pain syndromes, a psychological evaluation should be part of the multidisciplinary evaluation to assess for emotional symptoms that may be associated with the chronic pain problem. A sexual history is also required because secondary sexual issues will often arise and the patient may need advice and management of these issues.

Various invasive and medical treatment options have been suggested for patients with urethral syndrome;⁶⁶ most are anecdotal clinical reports, and controlled clinical studies are urgently needed to assess which approach might be most successful for this painful disorder. Endoscopic and open surgical procedures have been suggested to eliminate a presumed urethral stenosis. Fulguration, scarification, resection, or cryosurgery has been considered to obliterate cystoscopically apparent urethritis. Bladder instillations with a variety of anti-inflammatory or cauterizing agents and systemic therapy with anticholinergics, α-adrenergic blockers, and muscle relaxants have been advocated. High rates of success were found with skeletal muscle relaxants or electrostimulation combined with biofeedback techniques.^58,65 Realizing the different surgical and nonsurgical treatment options discussed in the literature, a conservative treatment approach has been recommended as the first choice because this usually is as effective as surgery, less expensive, and, most importantly, less subject to risk.^61,67 A comprehensive multidisciplinary approach may be required.

TESTICULAR PAIN SYNDROME AND SPECIFIC, DISEASE-ASSOCIATED TESTICULAR PAIN

Similar to women who suffer from pain syndromes of the reproductive organs, men with chronic testicular pain are usually embarrassed to talk about it. Many patients cannot recall any precipitating event that led to the onset of the chronic pain syndrome. Specific disease-associated testicular pains include infection, tumor, testicular torsion, varicocele, hydrocele, spermatocele, trauma (bicycle accident), and previous surgical interventions.^68,69 The differential diagnosis includes referred pain from the ureter or the hip or lumbar facet joints (particularly the thoraco-lumbar area) and entrapment neuropathies of the ilioinguinal or genitofemoral nerve (such as with psoas muscle pathology, as well as groin pathology). Chronic testicular pain has been reported as a complication of vasectomy.⁷⁰ This chronic genital pain syndrome is usually not associated with erectile or ejaculatory dysfunction.⁶⁸