Gender and chronic pelvic pain

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5 Gender and chronic pelvic pain

Maria Adele Giamberardino, Giannapia Affaitati, Raffaele Costantini

Introduction

Pain arising from the pelvic area, especially recurrent or chronic, is very frequent epidemiologically, and an important reason for patients seeking medical care. Benign or malignant in nature, it can be of different origins (i.e. musculoskeletal, neuropathic or visceral), but that deriving from internal organs is undeniably a prominent form, responsible not only for chronic suffering of patients but also for notable disability (Hubscher et al. 2007, Moore & Kennedy 2007). This chapter is intended to focus on the clinical profile, pathophysiology and treatment of paradigmatic forms of non-cancer pain from the pelvic viscera, with particular attention to recurrent/chronic pain from the reproductive area in both females and males. As an indispensable premise to this topic, general considerations will be made on the role of sex hormones on pain perception in the context of gender differences in pain.

The use of the terms ‘sex’ and ‘gender’ has generated much debate in the literature (LeResche 1999), some suggesting that ‘sex’ should strictly refer to biological aspects of the person and gender to his/her psychosocial identity (Snidvongs & Holdcroft 2008).

However, since strong mutual influences between biological and psychosocial aspects are undeniable in determining individuals’ responses to a variety of triggers, including those for pain, the terms ‘sex’ and ‘gender’ will here be used interchangeably.

Gender and pain: The role of sex hormones

After being neglected for a long period of time, the relationship between gender and pain has in recent decades become the subject of a huge number of studies in both the experimental and clinical context (Fillingim et al. 2009). Epidemiological investigation clearly shows that a number of clinical pain conditions – especially chronic – are more frequent in women than in men (e.g. chronic tension headache, migraine, facial and temporomandibular pain, musculoskeletal pain, pain from osteoarthritis and rheumatoid arthritis, and fibromyalgia) (Kuba & Quinones-Jenab 2005). Many of these show symptom fluctuations with the phases of the female cycle during the reproductive years, mostly with increased pain in the perimenstrual period (Allais & Benedetto 2004, Pamuk & Cakir 2005, Heitkemper & Chang 2009).

Women also present more intense and long-lasting pain complaints than men even for conditions occurring with similar frequency in the two sexes. In addition, there is also some suggestion that pain intensity expressed postoperatively and after several interventional procedures may be more intense in women compared to men (Filllingim et al. 2009).

Differences between the two sexes have also been found in experimental pain; though the results of the various studies in the literature are not always unequivocal, on the whole the bulk of human research performed in this area indicates greater pain sensitivity in women than in men in relation to the majority of pain modalities applied at both somatic and visceral levels (Arendt-Nielsen et al. 2004). More recent clinical investigation has focused on the women’s compared with the men’s responses to analgesic medications – especially opioids and NSAIDs – and to their side-effects (Fillingim & Gear 2004). They have shown significant differences in some cases, though more studies (with more homogeneous protocols) are needed in this specific field to completely clarify the issue (Snidvongs & Holdcroft 2008).

These sex differences in clinical (mostly) and experimental pain as well as in response to pain therapy are likely to be complex and multifactorial, involving a number of biological, sociocultural and psychological variables whose thorough and detailed analysis is far beyond the scope of this text (see Fillingim et al. (2009) for review). Attention will, however, be paid to sex hormones, as they are obviously among the major candidates to explain sex differences in pain (Fillingim & Ness 2000).

Sex hormones and pain

The three main sex hormones (i.e. oestrogen, progesterone and testosterone) are functionally active in both sexes, but their absolute levels and temporal fluctuations differ considerably in males and females (Berkley 1997, Berkley & Holdcroft 1999, Cairns & Gazerani 2009). Females undergo vast hormonal changes during puberty, pregnancy and menopause and cyclic hormonal fluctuations during the ovarian cycle in the reproductive phase of life. Males are instead exposed to less marked fluctuations in hormone levels across the lifespan, with the most significant change being the reduction of testosterone with ageing (Fillingim et al. 2009). Among the many body function parameters influenced by sex hormones, pain perception holds an important place, although there is not always universal agreement about how and to what extent this happens throughout the lifespan nor about the pathophysiology of these differences (Giamberardino 2000). In women, many painful conditions vary in their incidence, disappearance and prevalence as a function of puberty, pregnancy, menopause and ageing and, as already mentioned, during the reproductive years different forms of pain also vary with the phase of the menstrual cycle, mostly exacerbating in the perimenstrual period. In men, some pain disorders also show different profiles in the various stages of life (Berkley 2005, Cairns & Gazerani 2009, Fillingim et al. 2009).

Progesterone is mostly associated with analgesia because some pain conditions in humans – such as migraine and temporomandibular pain – disappear or improve during pregnancy or the midluteal phase of the menstrual cycle, and other pains are reduced in animals during lactation (when progesterone levels are high), and some anaesthetics are progesterone-based (e.g. alphaxolone) (Berkley & Holdcroft 1999, Silberstein 2004, LeResche et al. 2005, Brandes 2006, Craft 2007). Oestrogen has also been associated with analgesia, since some pain conditions increase when oestrogen decreases. For instance, as the oestradiol level sharply declines postpartum, the frequency of migraine attacks increases (Sances et al. 2003) and after the menopause, when oestrogen declines, several pain complaints – such as orofacial pain and vaginal pain – increase (LeResche et al. 2003, Fillingim et al. 2009). Similarly, testosterone promotes analgesia, its decline with ageing in men being consistently associated with an increase in a number of pains, such as angina or muscle pain (Berkley & Holdcroft 1999, Vecchiet 2002). For each of these examples, however, either a lack of effects or contrasting examples can be found, such as the decrease in postmenopausal women of musculoskeletal pain, chronic widespread pain and fibromyalgia, and in postmenopausal women and older men of abdominal pain (including irritable bowel syndrome, IBS) migraine and tension headaches, in parallel with a decrease in oestrogen, progesterone and testosterone. Another example is the emergence of cluster headaches in men at puberty, when testosterone increases (Berkley & Holdcroft 1999, LeResche et al. 2003, Kuba & Quinones-Jenab 2005). Exogenous hormone use has also been associated with change in several pain patterns. Women under oral contraceptive treatment have an increased risk for development of temporomandibular (TMD) pain and carpal tunnel syndrome.

Postmenopausal women under hormone replacement are at increased risk of back pain and TMD pain (LeResche et al. 1997, Ferry et al. 2000, Musgrave et al. 2001), but also discontinuation of this therapy is associated with higher levels of reported pain or stiffness (Ockene et al. 2005). Likewise, after sustained oestradiol administration, migraine attacks are precipitated by oestradiol withdrawal (Lichten et al. 1996). An interesting study in transsexuals taking hormones to acquire characteristics of the opposite sex has shown changes in pain responses, with over 30% of those taking oestradiol/antiandrogen developing chronic pain and 50% of those taking testosterone reporting improvement of chronic pain (headache) present before start of treatment (Aloisi et al. 2007). Thus both administration and withdrawal of exogenous oestrogens – but not testosterone – appear associated with an increased risk of chronic pain.

All these apparent contradictions can, at least partially, be accounted for by the fact that the overall hormonal effects on clinical pain expression depend more on the concentration of one hormone relative to the others than on its absolute values (Fillingim et al. 2009; see also Giamberardino 2000). The modulation of pain perception by sex hormones is probably the result of a combination of factors, among which the hormonal influences on metabolism (with implications for drug action), the immune system (with implications for painful autoimmune diseases, up to nine times more common in women), trauma-induced inflammation (modulated by sex hormones), the hypothalamic–pituitary axis (with implications for the interactions between stress and pain), and nervous and cardiovascular systems (Fillingim et al. 2002, al’Absi et al. 2004, Aloisi & Bonifazi 2006, Craft 2007, Straub 2007).

As already discussed, however, sex hormone effects on pain perception cannot be separated from the many other variables that affect pain modulation. Of particular importance are social and cultural factors, which can entail profound diversities in men and women (both patients and physicians) in their attitude towards and approach to painful symptoms, especially regarding particular forms of pain such as those arising from the pelvic area (see below) (Myers et al. 2003).

Visceral pelvic pain

The global incidence of pelvic pain is six times higher in women than in men, the difference being mostly due to pain originating from internal organs (Luzi 2002, Moore & Kennedy 2007). Viscera of the pelvic cavity belong to the genital, digestive and urinary tracts. The genital organs include ovaries, Fallopian tubes, uterus and upper vagina in women, ejaculatory ducts and vas deferens in men; the digestive organs consist of the sigmoid colon, rectum and a few coils of the small intestine; the urinary organs include the terminal parts of the ureters, the urinary bladder and pelvic urethra (Giamberardino 2000). Pain arising from the various organs of the pelvic cavity can be classified into three main categories:

1. Pelvic pain from sex-specific internal organs (female or male reproductive organs);

2. Pelvic pain from non-sex-specific internal organs (pelvic portion of the digestive and urinary tracts); and

3. Mixed pelvic pain (originating from both the reproductive organs and the digestive and/or urinary tracts, as well as from non-visceral structures) (Box 5.1).

Each of the recurrent/chronic visceral pain conditions from the pelvic area has its own specificities; however, common characteristics exist, which are typical of visceral pain in general. A brief summary of these characteristics is provided in the section below.

Visceral pain

The clinical presentation of pain from internal organs typically varies with time. In the first phases of a visceral algogenic process the symptom is very aspecific, always perceived in the same site – along the midline of the thorax or abdomen – whatever the viscus in question. It is vague and poorly discriminated, often described more as a sense of oppression or malaise rather than frank pain, and is accompanied by marked neurovegetative signs and emotional reactions (true visceral pain) (Procacci et al. 1986, Giamberardino 2005). In a second phase – after a few minutes or a few hours in the first episode or in a subsequent episode – it becomes referred to somatic structures of the body wall, in areas that are neuromerically connected to the viscus in question. Examples are the left chest area and ipsilateral upper limb for the heart, the lumbar region–flank–anterior abdomen spreading to the groin for renal colics, the upper right abdominal quadrant radiating towards the back at the inferior angle of the scapula for biliary colics, or the lowest abdominal quadrants and sacral region for pain from the female reproductive organs. In this phase, the symptom is very similar to that originating directly from the somatic structures; its visceral origin can thus be difficult to identify. In the referred pain area, hyperalgesia (i.e. an increased sensitivity to painful stimuli) typically develops. This is mostly localized in the skeletal muscle layer, but during particularly prolonged and/or intense processes it spreads upward to also involve the overlying superficial somatic tissues – the subcutis first, and finally the skin. Cutaneous hypersensitivity can become frank allodynia (pain perceived for normally non-painful stimuli) in extreme cases, as happens in peritonitis from painful abdominal conditions, such as a perforated appendicitis. Vice versa, in the course of the healing process of the painful visceral condition, the desensitization of the somatic area of referral proceeds from the surface downwards; the skin is the first to normalize and then the subcutis, with the muscle keeping some degree of residual hyperalgesia for a very long period of time (Giamberardino & Cervero 2007). The characteristics and temporal evolution of the referred hyperalgesia have been deducted from a number of studies in patients with visceral pains of various origin, such as urinary/biliary colics (from calculosis or diskinesia), IBS, dysmenorrhea, endometriosis. Most of this research has employed a combination of both clinical and instrumental procedures to assess the hypersensitivity, the latter involving measurement of pain thresholds to various stimuli (thermal, mechanical, chemical and electrical). Hyperalgesia is demonstrated by a significant lowering in pain detection threshold (Vecchiet et al. 1989, 1992, Giamberardino et al. 1994, 2001, 2005, Caldarella et al. 2006).

The global outcome of the studies performed indicates that hyperalgesia only appears in visceral conditions that are painful, irrespective of the nature of the visceral trigger (organic or dysfunctional), but is absent in any organic condition that is not algogenic. As already mentioned, the hyperalgesia is mostly a muscle phenomenon, involving the overlying subcutis and skin tissues only in more severe cases. Muscle hyperalgesia occurs early in the course of the visceral algogenic process (i.e. a few painful episodes are sufficient for it to manifest), and is accentuated by repetition of the episodes as the degree of pain threshold lowering becomes progressively more pronounced. Furthermore, it is of long duration; it normally outlasts the spontaneous pain – being detectable in the pain-free interval – and in most cases even the primary insult in the internal organ, though in a milder form. For instance, the majority of patients with urinary colics from calculosis who have passed the stone still present some degree of referred muscle hyperalgesia in the lumbar region months or even years after elimination (Vecchiet et al. 1992, Giamberardino et al. 1994).

Referred hyperalgesia is usually accompanied by trophic changes of local deep somatic wall tissues, mostly consisting of increased thickness of the subcutis and decreased thickness/section area of muscle, the latter testifying a tendency towards atrophy of muscle layers. These can be documented by clinical means (i.e. pinch palpation) but better quantified by ultrasonography. In symptomatic urinary and biliary calculosis, in fact, a significant increase in subcutis thickness and a significant decrease in muscle thickness have been found in the referred area (lumbar region and cystic point area, respectively) with respect to the contralateral non-affected area (Giamberardino et al. 2005, Giamberardino & Cervero 2007). Like the hyperalgesia, also trophic changes are set off by the algogenic impulses from the affected organ, since they are not detected in non-painful organic visceral conditions such as asymptomatic gallbladder calculosis. Unlike the hyperalgesia, however, they are not modulated by the extent of algogenic impulses from the visceral organ. In fact, they have been shown not to increase with the repetition of the painful episodes or decrease with their cessation; they seem to be a rather on–off phenomenon (Giamberardino 2005).

Referred pain with hyperalgesia has been attributed to phenomena of central sensitization involving viscerosomatic convergent neurons (Woolf & Salter 2000). The afferent barrage from the affected organ would increase the activity and response properties of these neurons, thus enhancing the central effect of the normal input from the somatic area of pain referral and accounting for the hyperalgesia (convergence-facilitation theory) (Cervero & Laird 2004, Sengupta 2009). (See discussion of these issues in Chapter 3.)

The visceral input would also activate a number of reflex arcs, whose afferent branch is represented by sensory fibres from the organ and whose efferent branch would be somatic towards the skeletal muscle and sympathetic towards the subcutis and skin of the referred area. Activation of these reflexes would contribute to the secondary hyperalgesia and also account for the local trophic changes (see Giamberardino et al. 2005). Hyperalgesia and trophic changes can be typically detected in referred pain areas from pelvic internal organs, as will be reported in the following sections.

Pelvic pain from sex-specific internal organs

Pain conditions from sex-specific visceral organs appear more frequently in women than in men, due to the more complex make-up of the pelvic region in females and the number of pathophysiological conditions directly or indirectly linked to their reproductive function (see Giamberardino 2000). Paradigmatic examples are primary dysmenorrhoea, chronic pain from endometriosis and pelvic inflammatory disease. There are, of course, also several examples of pain conditions of the reproductive organs in men (e.g. prostatitis, epididymitis, etc.); one of the most typical is chronic testicular pain, which represents an important medical problem from both a diagnostic and a therapeutic point of view (Wesselmann et al. 1999).

Pain from the female reproductive organs

Primary dysmenorrhoea

Primary dysmenorrhoea is defined as cyclic pain associated with menses in the absence of any documentable organic condition in the pelvic cavity. It is extremely common, estimated to occur in over 50% of all menstruating women in the world (Proctor & Farquhar 2006). The pain is believed to be caused by relative uterine ischaemia from hypercontractility of the myometrium, which is in turn the result of excess prostaglandins (prostaglandins would act by increasing uterine contractility and also by sensitizing nerve endings to the pain-producing effects of other compounds, such as bradykinins). By increasing the input towards the central nervous system, peripheral sensitization due to these mechanisms would then also favour the occurrence of central sensitization phenomena (Hubscher et al. 2007).

Symptoms usually start a few hours or days before bleeding, worsen as the menstrual flow begins and can last throughout the entire period of menses. Usually cramp-like in nature, the pain is typically perceived in the midportion of the lower abdomen but may also involve the lower back and upper thighs. Neurovegetative signs and emotional reactions, typical of visceral pain perception (i.e. nausea, vomiting, changes in heart rate, diarrhoea and anxiety) may precede or accompany the pain. Some dysmenorrhoeic patients also have midcycle pain (Giamberardino 2008). Pain of primary dysmenorrhoea can be very intense and, like other forms of pain from internal organs, is usually accompanied by tissue hypersensitivity in the somatic area of referral. This phenomenon was quantified in psychophysical studies in dysmenorrhoeic versus non-dysmenorrhoeic women using the technique of pain threshold measurement to electrical stimulation of skin, subcutis and muscle. Thresholds of all three tissues were lower than normal in dysmenorrhoeic women with respect to non-dysmenorrhoeic women, but the reduction was particularly accentuated in the muscle (rectus abdominis). The reduction was present not only in the painful period but also in the intervals between the cycles, testifying to the long duration of the hyperalgesic phenomenon. The muscle decrease proved more pronounced in women who had suffered from dysmenorrhoea for many years compared with women with dysmenorrhoea of recent onset, which, considering the repetitive nature of the condition, corresponds to a high or low number of painful episodes, respectively (Giamberardino et al. 1997).

Apart from hyperalgesia in the area of pain referral, however, dysmenorrhoeic women also showed a certain degree of muscle hypersensitivity in other body regions (diffuse muscle hyperalgesia), similar to the pattern observed in women affected with fibromyalgia (Russell & Larson 2009). Indeed, dysmenorrhoea is a significantly more frequent occurrence in fibromyalgia patients than in the general population (women with fibromyalgia syndrome have a fivefold higher probability to have dysmenorrhoea) (Shaver et al. 2006), a circumstance that has triggered scientific speculation about a common pathophysiological feature in the two conditions, consisting of a tendency to develop a state of central sensitization (Giamberardino 2008), which a generalized lowering in pain threshold would be proof of. Fibromyalgia is not the only frequent comorbidity for dysmenorrhoea. It is estimated, in fact, that about 50% of dysmenorrhoea patients have comorbidities also with other chronic pain conditions, such as IBS, interstitial cystitis (IC) or headache (Altman et al. 2006, Stanford et al. 2007, Watier 2009).

It is worth noting that also these conditions are characterized by a tendency to a generalized hypersensitivity to painful stimuli, thus suggesting once more that dysmenorrhoea is part of the wide spectrum of the so-called ‘functional disorders’ whereby central sensitization phenomena play a crucial role (Giamberardino 2008). Primary dysmenorrhoea needs to be differentiated from the pain complaints of premenstrual syndrome (PMS), a recurrent disorder occurring in the luteal phase of the menstrual cycle, estimated to affect up to 75% of women of childbearing age (Zaafrane et al. 2007). This disorder, a complex of somatic and psychological symptoms, is still incompletely explained pathophysiologically, but it has recently been put into relationship with overbreathing, a typical female syndrome (Slatkovska et al. 2006, Sauty & Prosper 2008; see also Chapters 11 and 12); in women with PMS the sensitivity of the respiratory centre to CO₂ would be increased more than normal by secretory products of the corpus luteum, resulting in hyperventilation. In addition, Ott et al. (2006) suggest that: ‘some symptoms of PMS may be caused by chronic hyperventilation’. Treatment of primary dysmenorrhoea is mainly performed with NSAIDs, although it is estimated that over 30% of women fail to show any improvement. Other measures are vitamins, magnesium, oral contraceptives and, in extreme cases, surgery (e.g. presacral neurectomy) (Proctor & Farquhar 2006).

Endometriosis

Endometriosis is defined as the presence of endometrial tissue in abnormal locations in the abdominal/pelvic cavity. This condition is estimated to affect 7–10% of all women of reproductive age in the world, with the most common sites of endometrial lesions being ovaries, uterine tubes, cul-de-sac, supporting ligaments of the uterus, pelvic peritoneum, rectovaginal septum, cervix and bowel surface (Berkley et al. 2005). The pathophysiology of endometriosis is still partly unknown. Hypotheses are retrograde menstruation, lymphatic system spread or haematogenous spread (Hubscher et al. 2007).

The clinical presentation of endometriosis is variable as regards pain. Though all women with the condition present infertility or subfertility, vaginal hyperalgesia and dyschezia, not all have spontaneous pain. Some are entirely asymptomatic, a number of them have secondary dysmenorrhoea, others show chronic pelvic pain (CPP). There is usually no correlation between the extent of the lesions and the amount of pain experienced, with minor lesions sometimes being the reason for intense pain and major lesions being asymptomatic. The mechanisms of pain are also not completely known, but probably involve more than one factor, including excess prostaglandin production, increased peritoneal sensitivity, chemical irritation of the peritoneum and bleeding in sites of endometriosis (Berkley 2005).

Like primary dysmenorrhoea sufferers, women with symptomatic endometriosis present abdomino-pelvic hyperalgesia, especially at muscle level, and also a generalized state of deep tissue hypersensitivity (Bajaj et al. 2003). As for primary dysmenorrhoea, it is worth noting that also endometriosis presents a high degree of co-morbidity with other pain conditions characterized by a generalized hypersensitivity to pain. In fact, women with endometriosis have higher rates of fibromyalgia (5.9 versus 3.4%, P < 0.0001), headache (endometriosis is significantly more common in migraineurs than in controls: 22% vs 9.6%, P < 0.01) but also IBS, IC and vulvodynia (Chung et al. 2005, Tietjen et al. 2007, Nyholt et al. 2009). Treatment of endometriosis remains a challenge for the medical community as no therapeutic option so far available has proven completely satisfactory. The choice is among pituitary inhibitory hormones, danazol, high-dose progesterone for medical treatment; laser during laparoscopy, surgical severance of the uterocervical plexus of the superior hypogastric plexus (presacral neurectomy) for the non-medical treatment. Symptomatic treatment of secondary dysmenorrhoea is similar to that for primary dysmenorrhoea, mainly with NSAIDs. A new possibility currently under evaluation in animal models involves drugs reducing blood supply to the ectopic growths (Ferrero et al. 2006).

Pelvic inflammatory disease

Pain associated with infection and inflammation of the female reproductive organs (pelvic inflammatory disease, PID) is of great clinical significance and a common cause of infertility, chronic pain and ectopic pregnancy (Haggerty & Ness 2008). It is the most common gynaecologic reason for admission to hospital in the USA; each year, in fact, at least 1 million American women are diagnosed with PID and more than 200 000 are hospitalized, with substantial healthcare costs (Wesselmann et al. 1999, Ross 2008, Sweet 2009). An ascending genital infection is generally the primary cause of PID. The aetiology is multimicrobial, including both sexually transmitted organisms – primarily Neisseria gonorrhoeae and Chlamydia trachomatis – and microorganisms found in the endogenous flora of the vagina and cervix, including anaerobic and facultative bacteria, many of which are associated with bacterial vaginosis (Haggerty & Ness 2008, Sweet 2009). Genital tract mycoplasms, mostly Mycoplasma genitalium, may also be implicated. Serious consequences of these upper genital inflammations include chronic pelvic pain in about 30% of patients (Moore & Kennedy 2007); it is estimated that while overall a woman has about a 5% risk of having chronic pelvic pain in her lifetime, patients with a previous diagnosis of PID have a fourfold increased risk of this complication (Ryder 1996). As for other forms of visceral pain, in PID, severe hyperalgesia often develops in muscles of the lower abdominal quadrants and pelvic area. This hyperalgesia normally outlasts the spontaneous pain and persists for a long time, to the point that the affected women may remain chronically hypersensitive in these somatic areas (Giamberardino 2000). Diagnosis of PID is challenging, mostly resulting from a combination of symptoms and signs and documentation of a polymicrobial aetiology. Due to the potential of serious sequelae, a low threshold for diagnosis and thus of treatment of acute PID is recommended (Haggerty & Ness 2008). Therapy should consist of wide-spectrum antibiotic regimens (oral or parenteral) that provide adequate coverage against the implicated microorganisms (Sweet 2009).

Pain from the male reproductive organs (See also Chapters 12 & 15)

Prostatitis/prostatodynia

Among the various forms of prostatitis, as defined by the NIH (Wagenlehner et al. 2009), chronic prostatitis, also called chronic pelvic pain syndrome (CPPS), is one of the most relevant regarding the pain problem. This syndrome is defined as pelvic pain for more than 3 of the previous 6 months, urinary symptoms and painful ejaculation, without documented urinary tract infections from uropathogens. It affects 10–15% of the male population. The aetiology is poorly understood. It is probably the consequence of an infectious or inflammatory initiator that results in neurological injury and eventually pelvic floor dysfunction (increased pelvic muscle tone). It is important to operate a differential diagnosis with chronic bacterial prostatitis through cultural examination. The therapy involves firstly a 4–6-week course of a fluoroquinolone, which provides relief in 50% of cases, and secondly NSAIDs and α-blockers for urinary symptoms. Pelvic floor training/biofeedback is also used. Minimally invasive surgical treatment may be necessary for treatment of refractory patients (Hubscher et al. 2007, Murphy et al. 2009).

Chronic orchialgia

Chronic orchialgia is defined as ‘intermittent or constant, unilateral or bilateral testicular pain lasting >3 months that significantly interferes with the daily activities’. It may occur at any age but the majority of patients are 20–30 years old (Granitsiotis & Kirk 2004). It is one of the most vexing problems for men and their treating physician (Wesselmann et al. 1999, Hubscher et al. 2007). The exact incidence and prevalence of this chronic pain syndrome are not known. The majority of patients are in their mid- to late 30s but chronic testicular pain has been described from adolescence to old age. In nearly 25% of the patients with this condition pain starts spontaneously in the absence of a clear precipitating event. Secondary causes of chronic orchialgia include infection, tumour, testicular torsion, varicocele, hydrocele, spermatocele, trauma or previous surgery. Referred pain from the ureter or the hip has also been reported as a cause of testicular pain, although other aetiologies cannot be excluded (Hubscher et al. 2007). Chronic orchialgia can be unilateral or bilateral. Some patients have constant pain; in others the pain is intermittent, either spontaneous or precipitated by certain movements or pressure on the testis. The pain may be confined to the scrotal contents or radiate to the groin, penis, perineum, abdomen, legs and back. The diagnosis is based on the clinical history and physical examination (urological/neurological). Treatment of this kind of patient requires identification of the underlying aetiology. However, when this is not possible (in 25% of cases, as already stated) several medical and non-medical treatments have proven beneficial, for instance a trial of antibiotics and NSAIDs (possible occult inflammatory processes), low-dose antidepressants, anticonvulsants, opiates or lumbar sympathetic blocks. Complete resolution of the symptomatology is, however, difficult (Sinclair et al. 2007, Baranowski 2009).

Pelvic pain from non-sex-specific visceral organs

Numerous pain conditions can affect the pelvic portion of the digestive and urinary tracts. We report here two paradigmatic examples of conditions for which no specific ‘organic’ cause has, to date, been identified: IBS and IC.

Irritable bowel syndrome

IBS is a chronic episodic medical condition characterized by abdominal/pelvic pain or discomfort and altered bowel habits in the absence of a detectable organic disease. It may present with diarrhoea and/or constipation, and is part of the spectrum of functional gastrointestinal disorders. IBS has a prevalence of 9–23% in the general population and accounts for up to 50% of diagnoses made by gastroenterologists. It affects women four times more than men, with a female predominance also in greater symptom severity. Its age distribution is unclear; some studies report a higher prevalence in the young and a decrease with age. This condition has a large impact on quality of life, with consequent high direct and indirect healthcare costs (Chang et al. 2006; Chang & Harris 2007). The pathophysiology of IBS is still incompletely known but is probably complex and multifactorial. A sensory disturbance has been hypothesized, in terms of an altered processing of the painful signal (visceral hyperalgesia), though it is still debated if this disturbance occurs primarily in the central nervous system or is triggered, at least initially, by a peripheral event, such as an infection (peripheral sensitization followed by central sensitization). Among specific molecules possibly involved in pain pathogenesis of IBS, serotonin (5-HT) has received most attention as it is an important player in the normal peristaltic reflex of the gut and can also sensitize visceral nociceptors and facilitate transient receptor potential family V receptor 1 (TRPV1) function. The role of a genetic predisposition is controversial (Mathew & Bhatia 2009, Van Oudenhove & Qasim 2009). IBS diagnosis is at present performed on the basis of Rome III criteria, i.e. recurrent abdominal pain or discomfort of at least 3 days/month in the last 3 months associated with two or more of the following: improvement with defecation, onset associated with a change in frequency of stools, onset associated with a change in form (appearance) of stool. The criteria need to be fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis (see Grundmann & Yoon 2010). Alarm symptoms (e.g. weight loss, fever, rectal bleeding, steatorrhoea, lactose/gluten intolerance) suggest the possibility of a structural disease, such as colon cancer, inflammatory bowel disease or malabsorption disorders (e.g. coeliac sprue), but do not necessarily exclude a diagnosis of IBS. The onset of IBS is usually precipitated by disruption of gastrointestinal function secondary to infection, dietary factors, lifestyle changes or psychological stress (IBS patients report a higher prevalence of sexual, physical and emotional abuse compared to healthy individuals). The spontaneous pain is described as a cramping, aching abdominal sensation whose severity ranges from mild and intermittent to severe and continuous. It can be precipitated by meals and improved by defecation. In female patients it is influenced by the menstrual cycle, with an increase immediately before and during menses. The abdominal painful areas typically enlarge with the progression of the disease. Abdominal pain is also evoked by intestinal transit (e.g. postprandial colonic contractions, unnoticed by controls) and endoscopic procedures. A number of clinical conditions occur more frequently in IBS than in the general population (comorbidities), such as psychiatric disorders (prevalence 40–90% in IBS patients), FMS (prevalence 31.6% in women with IBS), recurrent/chronic pelvic pain (prevalence of dysmenorrhoea 50% in women with IBS), chronic fatigue syndrome, interstitial cystitis, back pain, temporomandibular joint pain, headache (see Giamberardino 2008). IBS patients have abnormal reactivity to painful stimuli at both visceral and somatic level, particularly (1) lowered pain thresholds to mechanical and electrical stimuli of the gut in the majority of cases (visceral hyperalgesia) and (2) lowered pain thresholds in skin, subcutis and muscle in somatic abdominal areas of pain referral. In somatic areas outside the sites of pain referral, pain thresholds are lowered in subcutis and muscle while controversial results have been found in skin, with normal, higher than normal or lower than normal pain thresholds (thermal, mechanical electrical stimuli) (Caldarella et al. 2006). IBS typically lasts for the entire life of the patient, though a mild control of the symptoms can be achieved through treatment. This is typically multimodal, involving: appropriate diet (careful analysis of potential food triggers), traditional pharmacologic therapy (including bulking agents, antispasmodics, tricyclic antidepressants and other psychotropic agents, and laxatives), serotoninergic agents (5-HT3 receptor antagonists, 5-HT4 receptor agonists, combination 5-HT4 agonist and 5-HT3 antagonist), behavioural and psychological therapy (Heizer et al. 2009) .

Interstitial cystitis/painful bladder syndrome

Interstitial cystitis is a clinical syndrome characterized by urinary frequency and urgency, nocturia and suprapubic pain, without an identifiable organic cause, such as a bacterial infection (Theoharides et al. 2008). Reports on its prevalence (0.01–0.5% or higher) and female/male ratio (from 5:1 to 10:1) vary in different studies due to variations in disease definition and diagnostic criteria in the course of the years (Parsons et al. 2007). The typical age of onset is 40 years. It is a vexing condition and it normally takes 5–7 years and four or five specialist consultations for patients to receive a diagnosis. Over 70% of patients with IC present painful comorbidities: dysmenorrhoea, CPP, IBS, fibromyalgia and other rheumatic diseases (Alagiri et al. 1997; see also Giamberardino 2008). The aetiology and pathogenesis of IC are still undetermined. The present theories involve: deficiency in the surface glycosaminoglycan–mucin layer, allowing increased amounts of some unspecified toxic substance to permeate the bladder wall, causing inflammation (and eventually ulcers: Hunner’s ulcers) and pain; altered immunologic response/allergic reaction (elevated number of intravesical mast cells); neurogenic disorder (i.e. a chronic neurogenic inflammation of the bladder); and nociceptive disorder (visceral hyperalgesia). According to the latter, IC would not substantially differ from conditions like IBS, where after an initial triggering event determining visceral hyperalgesia, the hypersensitivity then continues to be sustained by central mechanisms of amplification of the pain signal (central sensitization) (Kelada & Jones 2007). The symptoms of IC are of variable intensity, but can reach devastating levels in some cases: intense suprapubic burning pain, urgency, incontinence, vaginal pain on intercourse, increased urinary frequency up to 60 times/day and 30 times/night (CPP). Symptoms are often triggered by some foods, they are progressive and worsen with time. They can greatly compromise the quality of life and be the cause of severe depression. The diagnosis is based on the clinical features and exclusion of other causes, cystoscopy only being confirmatory. The therapy to date is empirical, palliative and often scarcely effective. Changes in dietary habits, such as avoiding coffee, chocolate, alcohol, etc. are recommended, together with psychotherapy, drugs (e.g., tricyclic antidepressants) and intravesical instillations of hyaluronic acid (Nickel 2000).

Mixed pelvic pain

This category includes substantially two groups of conditions: CPP of mixed origin and pain from viscerovisceral hyperalgesia (Giamberardino 2008).

Chronic pelvic pain of mixed origin

This is a typical female condition, defined as pain in the lowest abdominal quadrants that persists for at least 6 months, continuous or intermittent, not exclusively associated with menstruation or sexual intercourse. It affects over 25% of all gynaecological patients and was estimated to be the cause of 5–10% of all laparoscopies and 20% of all hysterectomies up to 10 years ago. Though its aetiology is scarcely known, it is thought to be due to a combination of pelvic algogenic conditions, visceral (mostly dysmenorrhoea/endometriosis, but also IBS or IC), musculoskeletal and neuropathic. The therapy is still highly unsatisfactory, as a consequence of the limited knowledge about pathophysiological mechanisms (Chung et al. 2005, Altman et al. 2006, Butrick 2007, Montenegro et al. 2008).

Chronic pelvic pain from viscerovisceral hyperalgesia

Viscerovisceral hyperalgesia is a phenomenon consisting of an enhancement of painful symptoms, both direct and referred, due to the interaction between two affected internal organs that have at least partially overlapping sensory projections, for instance heart and gallbladder (common projections: T5), but more specifically in the case of pelvic pain, uterus and colon (T10–L1), or uterus and urinary tract (T10–L1) (Giamberardino et al. 2010). Women with dysmenorrhoea and IBS have been shown to complain of more menstrual pain and referred pelvic muscle hyperalgesia than women with dysmenorrhoea without IBS. They also report more abdominal pain from intestinal transit and referred abdominal muscle hyperalgesia than women with IBS without dysmenorrhoea. Effective hormonal treatment of dysmenorrhoea results in improvement also of IBS symptoms, while dietary treatment of IBS, if able to improve IBS, is also capable of ameliorating pain from dysmenorrhoea. Similarly, women with dysmenorrhoea and urinary calculosis report more menstrual pain, urinary colics and referred pelvic and lumbar muscle hyperalgesia than women with either dysmenorrhoea or urinary calculosis only, over a comparable period of time. Effective hormonal treatment of dysmenorrhoea improves the urinary pain, while calculosis treatment via extracorporeal shock wave lithotripsy also relieves the dysmenorrhoea (see Giamberardino & Cervero 2007). Thus the concomitance of two painful conditions in different internal organs sharing at least part of their central sensory projection causes an enhancement of pain symptoms from both districts. The notable therapeutic implication is that the typical pain from one district can be modulated by treating not only the specific condition of that district but also that of the other organ. Of importance is that viscerovisceral hyperalgesia also occurs when one of the two visceral disorders is latent with respect to pain. For instance, asymptomatic endometriosis (discovered by chance at laparoscopy performed for infertility reasons) enhances pain perception from the urinary tract in women with urinary calculosis; over a comparable period of time, women with the two conditions complain of more colics and referred lumbar muscle hyperalgesia than women with urinary calculosis only. Laser treatment of endometriosis improves the urinary pain (Giamberardino et al. 2001). Mechanisms behind viscerovisceral hyperalgesia remain to be fully established. However, since viscerovisceral convergences have been documented in the central nervous system between different internal organs (e.g. afferent fibres from uterus, urinary bladder, vagina and colon converge upon the same sensory neurons), it is plausible that sensitization of these neurons occurs, due to the increased input from one internal organ (Berkley 2005, Pezzone et al. 2005, Winnard et al. 2006, Malykhina 2007, Brumovsky & Gebhart 2010). As a result, the central effect of the input from the second organ would be enhanced. Since neurons receiving visceral inputs also constantly receive somatic projections, the referred phenomena are also amplified (Cervero 2000). It is interesting to note that viscerovisceral hyperalgesia at pelvic level seems to occur preferentially in women. This circumstance triggers a number of questions about women being more prone than men to develop chronic pelvic pain conditions (see section below).

Are women more susceptible than men to chronic pain?

As so far discussed, pelvic pain is by no doubt much more frequent in women than in men, mostly in relation to the higher complexity of structure and function of the reproductive area. But are women also more prone than men to develop chronic pain conditions from this and other areas? Berkely (2005) raised the interesting point that one contributing factor to pain sex differences derives from the vagina and cervix providing ready access to internal pelvic structures, and thus ready access also to the entrance of a number of infectious agents (i.e. viruses, bacteria, etc.). This entails a greater propensity to develop a number of pelvic inflammatory conditions that, in turn, can increase the vulnerability in women of the T10–L1 (innervating uterus and cervix) and S2–S4 (innervating vagina and cervix) segments to morbidity (Bonica 1990). Repeated/persistent input from the periphery can then lead to central sensitization phenomena responsible for the evolution of pelvic pain conditions towards chronicity and also, by spreading of sensitization to other segments, to the development of more generalized pain states (such as fibromyalgia) which women present much more frequently than men (Abeles et al. 2007).

Whether or not the initiating factor is represented by infectious agents from the vaginal canal, as in Berkley’s hypothesis, the fact remains that the high number of acute/recurrent pain events from sex-specific organs in women – linked to their reproductive physiology – is a potential trigger for central neuroplastic changes in the pelvic segments. This, in turn, also facilitates phenomena of viscerovisceral hyperalgesia in the same domain, with mutual exacerbation of symptoms from the reproductive organs, and digestive and urinary tracts in the area, predisposing women compared with men to developing more complex and persisting painful conditions (Giamberardino 2008).

Further research in the field, also employing animal models of relevant pelvic pain conditions, such as the models of uterine inflammation and of endometriosis plus ureteral calculosis in the female rat (Wesselmann et al. 1998, Giamberardino et al. 2002), is needed to further elucidate mechanisms behind the higher susceptibility of women to chronic visceral pain.