3. EPIDEMIOLOGY, AETIOLOGY AND PATHOPHYSIOLOGY
3.1. Chronic visceral pain
Definition of pain
Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (IASP Taxonomy).
Introduction to chronic pelvic primary pain syndromes
Over the years much of the focus for CPPPS has been on peripheral-end-organ mechanisms, such as inflammatory or infective conditions. However, both animal and clinical research have indicated that many of the mechanisms for the CPPPSs are based within the CNS. Although a peripheral stimulus such as infection may initiate the start of a CPPPS condition, the condition may become self-perpetuating as a result of CNS modulation. As well as pain, these central mechanisms are associated with several other sensory, functional, behavioural and psychological phenomena. It is this collection of phenomena that forms the basis of the pain syndrome diagnosis and each individual phenomenon needs to be addressed in its own right through multi-specialty and multi-disciplinary care. Although ongoing peripheral organ pathology can produce persistent and chronic pain, the main focus of these guidelines is on CPPPSs in which no peripheral ongoing pathology (such as infection or neoplastic disease) is detected. The main exception is when pain is due to peripheral nerve damage.
No adequate data on incidence were found.
Across the world  chronic pain is prevalent, seriously affecting the quality of people’s social, family, and working lives, with differences between countries attributable to multiple causes, including study methodology.
A UK study found a prevalence of chronic pelvic pain of 14.8% in women over 25 years .
3.1.3. Influence on Quality of Life
Assessing QoL in pelvic pain patients is challenging due to the complex pathology, the multi-faceted nature of the complaints and the overlap between the different pelvic pain syndromes [22,23]. Pelvic pain syndromes have an impact in terms of QoL [24,25], depression, anxiety, impaired emotional functioning, insomnia and fatigue [24,26]. If these aspects are identified and targeted early in the diagnostic process, the associated pain symptoms may also improve. Addressing comorbidities will help in further improving QoL . Quality of life assessment is therefore important in patients with pelvic pain and should include physical, psychosocial and emotional tools, using standardised instruments where possible . Chronic pain is, in many countries, the leading cause of years lost to disability , although these figures are dominated by musculoskeletal pain and headache. Chronic pain is often associated with depression and other psychological problems; with loss or reduction of work and of ability to carry out domestic tasks; and, with substantial use of healthcare, often with disappointing outcomes.
No adequate data on costs were found.
3.1.5. Risk Factors and underlying causes
126.96.36.199. Risk factors
Risk factors include many different factors from various areas, including genetic, psychological state, recurrent physical trauma and endocrine factors.
The endocrine system is involved in visceral function. Significant life events, and in particular, early life events may alter the development of the hypothalamic-pituitary-adrenal axis and the chemicals released. Increased vulnerability to stress is thought to be partly due to increased corticotrophin-releasing hormone (CRH) gene expression. Up-regulation of CRH has been implicated in several pain states such as rectal hypersensitivity to rectal distension. This model suggests an action of CRH on mast cells. A range of stress-related illnesses have been suggested, e.g., IBS and BPS. There is evidence accumulating to suggest that the sex hormones also modulate both nociception and pain perception. Stress can also produce long-term biological changes which may form the relation between chronic pain syndromes and significant early life and adverse life events . Asking the patient about these events is important as they have an effect on a patient’s psychological wellbeing [29,30].
Genetics also play a role in assessing the risk of developing chronic pain. An individual who has one chronic pain syndrome is more likely to develop another. Family clusters of pain conditions are also observed and animals can be bred to be more prone to apparent chronic pain state. A range of genetic variations have been described that may explain the pain in certain cases; many of these are to do with subtle changes in transmitters and their receptors. However, the picture is more complicated in that developmental, environmental and social factors also influence the situation. Evidence that PBPS may have a genetic component has been presented in several identical twin studies, but genetics may contribute to less than one third of total variation in susceptibility to PBPS [31,32].
Studies about integrating the psychological factors of CPPPSs are few but the quality is high. Psychological factors are consistently found to be relevant in the maintenance of persistent pelvic and urogenital pain . Beliefs about pain contribute to the experience of pain  and symptom-related anxiety and central pain amplification may be measurably linked, as in IBS , and catastrophic thinking about pain and perceived stress predict worsening of urological chronic pain over a year [33,36]. Central sensitisation has been demonstrated in symptomatic endometriosis  and central changes are evident in association with dysmenorrhoea and increasingly recognised as a risk for female pelvic pain . The various mechanisms of CNS facilitation, amplification and failure of inhibition mean that there is no simple relationship between physical findings, pain experience and resulting distress and restriction of activities. Division of aetiology into organic vs. psychogenic is unscientific. Diagnoses that assign women’s pain to psychological origins due to scepticism about the reality or severity of their pain [39,40] undermines any therapeutic relationship . Pelvic pain and distress may be related  in both men and women ; as are painful bladder and distress . In a large population based study of men, CPPPS was associated with prior anxiety disorder . The only SR  of risk factors for chronic non-cyclical pelvic pain in women included, as well as medical variables: sexual or physical abuse (Odds Ratio (OR): 1.51-3.49); psychological problems such as anxiety (OR: 2.28; 95% Confidence Interval (CI): 1.41-3.70) and depression (OR: 2.69; 95% CI: 1.86-3.88); multiple somatic problems (OR: 4.83; 95% CI: 2.50-9.33 and OR: 8.01; 95% CI: 5.16-12.44).
Many studies have reported high rates of childhood sexual abuse in adults with persistent pain, particularly in women with pelvic pain . It is hard to establish a causal role for sexual abuse or trauma history, anxiety or depression in women with CPPPS [47,48], as the attribution of current pain to past sexual or physical abuse is associated both with current depression  and with current overall physical health . There is some evidence for a specific relationship between rape and CPPPS (and with fibromyalgia and functional gastrointestinal disorders) ; and, recent sexual assault may prompt presentation of pelvic pain [46,52]. Few studies have been found of sexual or physical abuse in childhood and pelvic pain in men, although it has known adverse effects on health , but men who reported having experienced sexual, physical or emotional abuse had increased odds (3.3 vs. 1.7) for symptoms suggestive of CPPPS . Both sexes should be screened for sexual abuse when presenting with symptoms suggestive of CPPPS, and clinicians should inquire about pelvic pain in patients who have experienced abuse .
188.8.131.52. Underlying causes
The mechanisms that serve as an underlying cause for chronic pelvic pain are:
1.Ongoing acute pain mechanisms  (such as those associated with inflammation or infection), which may involve somatic or visceral tissue.
2.Chronic pain mechanisms, which especially involve the CNS .
3.Emotional, cognitive, behavioural and sexual responses and mechanisms [55-57].
Symptoms and signs of neuropathic pain appear to be common in CPPPS patients and assessment of neuropathic pain should be considered in that group of patients. The presence or absence of endometriosis does not seem to change this .
Chronic pain mechanisms may include altered resting state neuromotor connectivity, for instance in men with chronic prostatitis/CPPPS .
Table 3 illustrates some of the differences between the somatic and visceral pain mechanisms. These underlie some of the mechanisms that may produce the classical features of visceral pain; in particular, referred pain and hyperalgesia.
Table 3: Comparison between visceral and somatic pain
Effective painful stimuli
Stretching and distension, producing poorly localised pain.
Mechanical, thermal, chemical and electrical stimuli, producing well localised pain.
Widespread stimulation produces significantly magnified pain.
Widespread stimulation produces a modest increase in pain.
Autonomic features (e.g., nausea and sweating) frequently present.
Autonomic features less frequent.
Pain perceived at a site distant to the cause of the pain is common.
Pain is relatively well localised and well recognised.
Referred cutaneous and muscle hyperalgesia is common, as is involvement of other visceral organs.
Hyperalgesia tends to be localised.
Low density, unmyelinated C fibres and thinly myelinated A∂ fibres.
Dense innervation with a wide range of nerve fibres.
Primary afferent physiology
Intensity coding. As stimulation increases, afferent firing increases with an increase in sensation and ultimately pain.
Two fibre coding. Separate fibres for pain and normal sensation.
50-90% of visceral afferents are silent until the time they are switched on.
These fibres are very important in the central sensitisation process. Silent afferents present, but form a lower percentage.
Play an important part in the hyperalgesia, viscero-visceral, viscero-muscular and musculo-visceral hyperalgesia.
Sensations not normally perceived become perceived and non-noxious sensations become painful. Responsible for the allodynia and hyperalgesia of chronic somatic pain.
Abnormalities of function
Central mechanisms associated with visceral pain may be responsible for organ dysfunction.
Somatic pain associated with somatic dysfunction, e.g., muscle spasm.
Central pathways and representation
As well as classical pathways, there is evidence for a separate dorsal horn pathway and central representation.
Classical pain pathways.
Ongoing peripheral pain mechanisms in visceral pain
In most cases of chronic pelvic pain, ongoing tissue trauma, inflammation or infection is absent [60,61]. However, conditions that produce recurrent trauma, infection or ongoing inflammation may result in chronic pelvic pain in a small proportion of cases. For example, out of a large cohort with acute bacterial prostatitis, 10.5% ended up with a state of CPPPS . It is for this reason that the early stages of assessment include looking for these pathologies . Once excluded, ongoing investigations for these causes are rarely helpful and indeed may be detrimental.
When acute pain mechanisms are activated by a nociceptive event, as well as direct activation of the peripheral nociceptor transducers, sensitisation of those transducers may also occur; therefore, magnifying the afferent signalling. Afferents that are not normally active may also become activated by the change, that is, there may be activation of the so-called silent afferents. Although these are mechanisms of acute pain, the increased afferent signalling is often a trigger for the chronic pain mechanisms that maintain the perception of pain in the absence of ongoing peripheral pathology (see below) .
There are a number of mechanisms by which the peripheral transducers may exhibit an increase in sensibility:
2.There may be an increase in the chemicals that stimulate the receptors of the transducers .
In general, the effect of 1 and 2 above is to lower the threshold and the effect of 3 above is to increase responsiveness to external stimuli. Some of the chemicals responsible for the above changes may be released from those cells associated with inflammation, but the peripheral nervous system may also release chemicals in the positive and inhibitory loops [65,66].
Central sensitisation as a mechanism in visceral pain
It is important to appreciate that nociception is the process of transmitting information to centres involved in perception of a stimulus that has the potential to cause tissue damage. Pain is far more complex and involves activation of the nociceptive pathways but also the emotional response. The brain may affect the modulation of pain pathways at the spinal cord level.
Neuronal sensitisation is responsible for a decrease in threshold and an increase in response duration and magnitude of dorsal horn neurons. It is associated with an expansion of the receptive field. As a result, sensitisation increases signalling to the CNS and amplifies what we perceive from a peripheral stimulus. For example, for cutaneous stimuli, light touch would not normally produce pain, however, when central sensitisation is present, light touch may be perceived as painful (allodynia). In visceral hyperalgesia (so called because the afferents are primarily small fibres), visceral stimuli that are normally sub-threshold and not usually perceived, may be perceived. For instance, with central sensitisation, stimuli that are normally sub-threshold may result in a sensation of fullness and a need to void or to defecate. Non-noxious stimuli may be interpreted as pain and stimuli that are normally noxious may be magnified (true hyperalgesia) with an increased perception of pain. As a consequence, one can see that many of the symptoms of PBPS and IBS may be explained by central sensitisation. A similar explanation exists for the muscle pain in FM.
It is now well accepted that there are both descending pain-inhibitory and descending pain-facilitatory pathways that originate from the brain . Several neurotransmitters and neuromodulators are involved in descending pain-inhibitory pathways. The main ones are the opioids, 5-hydroxytryptamine and noradrenaline.
The autonomic nervous system also plays a role in sensitisation. There is good evidence that damaged afferent fibres may develop a sensitivity to sympathetic stimulation, both at the site of injury and more centrally, particularly in the dorsal horns. In visceral pain, the efferent output of the CNS may be influenced by central changes (again, those changes may be throughout the neuraxis), and such modification of the efferent message may produce significant end-organ dysfunction. These functional abnormalities can have a significant effect on QoL and must be managed as appropriate.
Psychological mechanisms in visceral pain
Psychological processes of emotions, thought and behaviour involve networks rather than distinct centres. Some of these processes are sophisticated and others fundamental in evolutionary terms, and their interaction with pain processing is complex.
Various psychological processes affect pain neuromodulation at a higher level. Inhibiting or facilitating both the strength of the nociceptive signal reaching the consciousness and appraisal and interpretation of that signal, will also modulate the response to the nociceptive message and hence the pain experience. Further, descending pathways represent cognitive, emotional and behavioural states at spinal and peripheral levels. The psychological modulation of visceral pain probably involves multiple pathways: for instance, mood and attentional focus probably act through different areas of the brain when involved in reducing pain .
This psychological modulation may act to reduce nociception within a rapid time frame but may also result in long-term vulnerability to chronic visceral pain, through long-term potentiation. This involvement of higher centre learning may be at both a conscious and subconscious level, and is clearly significant in the supratentorial neuroprocessing of nociception and pain. Long-term potentiation  may occur at any level within the nervous system, so that pathways for specific or combinations of stimuli may become established, resulting in an individual being vulnerable to feeling pain from sensations that would not normally be experienced as painful.
An important review  of chronic pelvic pain in women dismantled the notion that women without relevant physical findings differ in psychological characteristics from women with relevant physical findings. Women with pelvic pain often have other non-pain somatic symptoms and current or lifetime anxiety and depression disorder ; they may have a history of physical or sexual abuse in childhood; but this is of unclear significance. Studies should avoid interpreting the absence of physical findings as evidence for psychological originis of the complaint (‘psychosomatic’ or ‘somatoform’ disorders). Pain studies describe multiple processes by which pain may spread across sites, or in time, including central sensitisation (see previous section), viscero-visceral cross sensitisation in relation to multiple pain sites , activation of the hypothalamic-pituitary axis and dysregulation of serotonergic pathways  that can render pain levels responsive to stress. Some pain problems which affect sexual activity are diagnosed as sexual problems (e.g., ‘dyspareunia’) when pain is the central problem and is not contingent on sexual activity alone . Better integration of sexology and mainstream psychology for pelvic pain in both men and women is needed, building on a biopsychosocial formulation [73,74].
The term psychosomatic symptoms can best be understood as multiple somatic symptoms not associated with, or indicative of, any serious disease process. Medical and surgical history may also be important .
Understanding the psychological components of pain
Psychological processes of emotions, thought and behaviour involve distributed networks, whose interactions with pain processing are complex, producing inhibition and facilitation of signal processing, appraisal, and response. Models that integrate psychological factors involved in maintaining persistent pelvic and urogenital pain with current neurobiological understanding of pain are few, but the quality is high (see Section 184.108.40.206).
There is no evidence that women with CPPPS without physical findings are primarily presenting a psychological problem . Anxiety and post-traumatic stress symptoms are common in some women with CPPPS [40,76] and with vulvar pain , and may account for substantial variance in health status, treatment use and treatment outcome; for instance, women’s expectations about vulvar pain on penetration predicted pain, sexual function and sexual satisfaction . Negative investigative findings do not necessarily resolve women’s anxieties about the cause of pain [79,80] and anxiety often focuses on what might be ‘wrong’. Depression may be related to pain in various ways, as described above. Until measures are available that are adequately standardised in patients with pain, assessment of anxiety and distress requires questions about the patient’s beliefs about the cause of pain, the hope that diagnosis will validate pain, the struggle with unpredictability, and the implications of pain for everyday life [81,82]. Reference to the studies of the IMMPACT group  is recommended for guidance on outcome measures suitable for pain trials.
Stress can modify the nervous system to produce long-term biological changes. These structural changes may be responsible for significant early life and adverse life events which are associated later with chronic pain syndromes . The patient should be asked about adverse life events that may produce these biological responses and affect general psychological well-being [30,84].
220.127.116.11. Clinical paradigms in visceral pain
Referred pain is frequently observed and its identification is important for diagnosis and treatment. Referral is usually somatic to somatic, or visceral to somatic. However, there is no reason why pain cannot also be perceived within the area of an organ with the nociceptive signal having arisen from a somatic area. Referred pain may occur as a result of several mechanisms but the main theory is one of convergence-projection. In the convergence-projection theory, afferent fibres from the viscera and the somatic site of referred pain converge onto the same second order projection neurons. The higher centres receiving messages from these projection neurons are unable to separate the two possible sites from the origin of the nociceptive signal .
Hyperalgesia refers to an increased sensitivity to normally painful stimuli. In patients that have passed a renal stone, somatic muscle hyperalgesia is frequently present, even a year after expulsion of the stone. Pain to non-painful stimuli (allodynia) may also be present in certain individuals. Somatic tissue hyperaesthesia is associated with urinary and biliary colic, IBS, endometriosis, dysmenorrhoea, and recurrent bladder infections. Primary vulvar pain syndromes are examples of cutaneous allodynia that, in certain cases, may be associated with visceral pain syndromes, such as BPS. Referred pain with hyperalgesia is thought to be due to central sensitisation of the converging viscero-somatic neurons. Central sensitisation also stimulates efferent activity that could explain the trophic changes that are often found in the somatic tissues.
Musculo-skeletal system and pelvic pain
In the urogenital pain syndromes, muscle tenderness and trigger points may be implicated as a source of pain. Central mechanisms are of great importance in the pathogenesis of this muscle hyperalgesia. The muscles involved may be a part of the spinal, abdominal or pelvic complex of muscles. It is not unknown for adjacent muscles of the lower limbs and the thorax to become involved. Pain may be localised to the trigger points but it is more often associated with classical referral patterns. As well as trigger points, inflammation of the ligaments and tendons to the bones (enthesitis) and of the bursa (bursitis) may be found . Certain postures affect the different muscles in different ways, and as a consequence, may exacerbate or reduce the pain. Stress has been implicated as both an initiator of pelvic myalgia and as a maintenance factor. As a result, negative sexual encounters may also have a precipitating effect .
The increased perception of stimuli in the viscera is known as visceral hyperalgesia, and the underlying mechanisms are thought to be responsible for IBS, PBPS and dysmenorrhoea. The mechanisms involved are often acute afferent input (e.g., due to infection) followed by long-term central sensitisation. Viscero-visceral hyperalgesia is thought to be due to two or more organs with converging sensory projections and central sensitisation. For instance, overlap of bladder and uterine afferents or uterine and colon afferents.
3.2. Pelvic pain
No adequate data on incidence were found.
18.104.22.168. Primary prostate pain syndrome
There is only limited information on the true prevalence of PPPS in the population. As a result of significant overlap of symptoms with other conditions (e.g., benign prostatic enlargement and PBPS), purely symptom based case definitions may not reflect the true prevalence of PPPS [86,87]. In the literature, population-based prevalence of prostatitis symptoms ranges from 1-14.2% [88,89]. The risk of prostatitis increases with age (men aged 50-59 years have a 3.1-fold greater risk than those aged 20-39 years).
22.214.171.124. Primary bladder pain syndrome
Reports of PBPS prevalence have varied greatly, along with the diagnostic criteria and populations studied. Recent reports range from 0.06-30% [90-99]. There is a female predominance of about 10:1  but possibly no difference in race or ethnicity [86,100,101]. The relative proportions of Hunner’s lesion and non-lesion disease are unclear. Incidence in studies has ranged from 5-50% [102-105]. There is increasing evidence that children under eighteen may also be affected, although prevalence figures are low; therefore, PBPS cannot be excluded on the basis of age .
126.96.36.199. Sexual pain syndrome
In the 1980s, an association between chronic pelvic pain and sexual dysfunction was postulated. In a review the relationship between Primary Prostate Pain Syndrome and health status, with influence on sexual activity, was addressed . In a Chinese study of men with chronic pelvic pain, 1,768 males completed the questionnaires. The overall prevalence of sexual dysfunction was 49%. Erectile dysfunction (ED) is the most investigated sexual dysfunction in PPPS patients. The reported prevalence of ED ranges from 15.1-48%, varying with evaluation tools and populations [108,109]. Erectile dysfunction was prevalent in 27.4% of Italian men aged 25-50 , 15.2% among Turkish men (significantly higher than in the control group)  and 43% among Finnish men with PPPS . The prevalence of ED was found to be higher in young men with PPPS than in the general population. According to other studies, men with pelvic pain had a higher chance of suffering from ED . A significant correlation between “chronic prostatitis”, chronic pelvic pain symptoms (measured by NIH-CPSI) and ED (measured by International Index of Erectile Function [IIEF]) was confirmed , while other studies using the same questionnaires were not able to confirm such a correlation [74,115]. Some studies also report ejaculatory dysfunction, mainly premature ejaculation [108,109,116,117].
In community-based studies in the UK , New Zealand  and Australia , a substantially larger proportion of the women with chronic pelvic pain reported dyspareunia (varying between 29-42%) than women without chronic pelvic pain (varying between 11-14%). Only a few studies have investigated sexual problems within clinical populations . Another study showed that all of the sexual function domains (desire, arousal, lubrication, orgasm, satisfaction, and pain) were significantly lower in women with chronic pelvic pain than in women without chronic pelvic pain . In line with the results of these community based studies, patients with chronic pelvic pain reported more sexual problems such as dyspareunia, problems with desire or arousal and lubrication than women without chronic pelvic pain [121,122]. One study of patients enrolled in chronic pain treatment programs in England has reported that 73% had pain-related sexual problems .
188.8.131.52. Myofascial pain syndromes
The relationship between muscular dysfunction (especially over-activity) and pelvic pain has been found in several studies . Rectal pain treated with pelvic floor muscle therapy is only relieved when patients learn to relax their pelvic floor muscles [125,126]. The vast majority (92.2%) of men visiting a tertiary centre for pelvic pain had dysfunction of the pelvic floor muscles. This finding was true regardless of evidence of inflammation (prostatitis or cystitis) . This relationship has been found in chronic prostatitis , PBPS  and vulvar pain . Dysfunction of the pelvic floor directly affects function of the pelvic viscera and vice versa. Both systems can act as the primary signal to the spinal cord, with a cascade of reactions ascending to the CNS as a result. The muscle itself ends up shortened, leading to restrictions even in a relaxed state.
3.2.3. Influence on Quality of Life
Data on the influence on QoL will be included in a future version of the guidelines.
No adequate data on costs were found.
3.2.5. Risk factors and underlying causes
The risk factors are unspecific for most of the pain syndromes in the pelvic area. They are described in Section 184.108.40.206. The underlying causes, including the mechanisms for the different clinical pain syndromes are described here.
220.127.116.11. Primary prostate pain syndrome
Pain is the main symptom in PPPS. As a common feature of primary chronic pain syndromes, no single aetiological explanation has been found. One explanation is that the condition probably occurs in susceptible men exposed to one or more initiating factors, which may be single, repetitive or continuous. Several of these potential initiating factors have been proposed, including infectious, genetic, anatomical, neuromuscular, endocrine, immune (including autoimmune), or psychological mechanisms. These factors may then lead to a peripheral self-perpetuating immunological, inflammatory state and/or neurogenic injury, creating acute and then chronic pain. A study showed that chronic but not acute histological inflammation of the prostate was significantly associated with symptomatic progression . Based on the peripheral and the CNS, sensitisation involving neuroplasticity may lead to a centralised neuropathic pain state . This could also explain why tissue damage is not usually found in PPPS. There is growing evidence for a neuropathic origin and association with CNS changes of pain in PPPS, and anxiety appears to be a risk factor for its
18.104.22.168. Primary bladder pain syndrome
An initial unidentified insult to the bladder, leading to urothelial damage, neurogenic inflammation and pain is thought to be a trigger of PBPS. However, PBPS might be a local manifestation of a systemic disorder. No infection has as yet been implicated. Nevertheless, urinary infections are significantly more frequent during childhood and adolescence, in patients with PBPS in adulthood . Experimental induction of chronic pelvic pain by O-antigen deficient bacterial strains supports the bacterial hypothesis . Pancystitis, with associated perineural inflammatory infiltrates, and mast cell count increase is an essential part of PBPS type 3 C , but is rare in non-lesion PBPS [30,68,136,137]. Cystoscopic and biopsy findings in both lesion and non-lesion PBPS are consistent with defects in the urothelial glycosaminoglycan (GAG) layer, which might expose submucosal structures to noxious urine components [138-144] and a consequent cytotoxic effect
[145,146]. Basic and clinical studies indicate that autonomic dysfunction with sympathetic predominance may be implicated in PBPS [147,148].
An association has been reported between PBPS and non-bladder syndromes such as FM, CFS, IBS, vulvodynia, depression, panic disorders, migraine, sicca syndrome, temporomandibular joint disorder, allergy, asthma and systemic lupus erythematosus [149-153].
Risk of PBPS correlates with a number of non-bladder syndromes in each patient . Recent work showing non-lesion PBPS to have significantly more FM, migraine, temporomandibular joint disorder and depression than PBPS type 3 C patients, which emphasises, the need for subtyping .
22.214.171.124. Primary scrotal pain syndrome
Often scrotal pain is not associated with any specific pathology. Pain is perceived in the testes, epididymis, or the vas deferens. The ilioinguinal, genitofemoral and the pudendal nerves innervate the scrotum . Any pathology or intervention at the origin or along the course of these nerves may result in pain perceived in the scrotum .
Two special forms of scrotal pain syndrome can be described. The first is post-vasectomy scrotal pain syndrome which occurs following vasectomy. The mechanisms are poorly understood, and for that reason it is considered by some a special form of primary scrotal pain syndrome. Incidence of post-vasectomy pain is 2-20% among all men who have undergone a vasectomy . In men with post-vasectomy pain, 2-6% have a Visual Analogue Scale (VAS) score > 5 . In a large cohort study of 625 men, the likelihood of scrotal pain after six months was 14.7%. The mean pain severity on a VAS score was 3.4/10. In the pain group, 0.9% had quite severe pain, noticeably affecting their daily life. In this cohort, different techniques were used to perform the vasectomy. The risk of post-vasectomy pain was significantly lower in the no-scalpel vasectomy group (11.7% vs. the scalpel group 18.8%) .
The second special form of scrotal pain is post-inguinal hernia repair pain. It is seen as a complication of hernia repair, but in trials it is seldom reported, or it is put under the term chronic pain (not specified). In studies that have explicitly mentioned scrotal pain, there was a difference in incidence between laparoscopic and open hernia repair. In almost all studies, the frequency of scrotal pain was significantly higher in the laparoscopic than in the open group [157,161]. In one particular study, there was no difference at one year but after five years, the open group had far fewer patients with scrotal pain . Inguinal hernia repair can lead to chronic post-surgical pain (CPSP) in up to 10% of patients at six months  and may present with groin and/or scrotal pain. Testicular injury is uncommon (< 1%) but if associated with pain, orchidectomy can lead to symptomatic relief in 2/3 of patients . Careful identification and preservation of nerves has been found to be associated with a reduced risk of chronic pain.
126.96.36.199. Primary urethral pain syndrome
Several mechanisms for the development of primary urethral pain syndrome have been proposed. The intimate relationship of the urethra with the bladder (both covered with urothelium) suggests that primary urethral pain syndrome may be a form of PBPS. Mechanisms thought to be basic for PBPS may also apply to the urethra. This means that the specific testing with potassium has been used to support the theory of epithelial leakage [165,166]. Another possible mechanism is neuropathic hypersensitivity following urinary tract infection . The relationship with gynaecological and obstetric aspects is unclear. In a small group of patients with urethral pain, it has been found that grand multi-parity and delivery without episiotomy were more often seen in patients with urethral syndrome, using univariate analysis .
188.8.131.52. Primary vaginal and vulvar pain syndromes
Pain in the vagina or the female external genital organs is often due to infection or trauma, as a consequence of childbirth or surgery. Pain is usually a precedent to dyspareunia. When the pain persists for more than three months, it can be diagnosed as primary vulvar pain syndrome previously known as “vulvodynia” or “chronic vaginal pain” with no known cause. It is still a poorly understood condition, and therefore difficult to treat.
There are two main sub-types of primary vulvar pain syndrome: generalised, where the pain occurs in different areas of the vulva at different times; and focal, where the pain is at the entrance of the vagina. In primary generalised vulvar pain syndrome, the pain may be constant or occur occasionally, but touch or pressure does not initiate it, although it may make the pain worse. In primary focal vulvar pain syndrome, the pain is described as a burning sensation that comes on only after touch or pressure, such as during intercourse.
The possible causes of primary vulvar pain syndrome are many and include:
- history of sexual abuse;
- history of chronic antibiotic use;
- hypersensitivity to yeast infections, allergies to chemicals or other substances;
- abnormal inflammatory response (genetic and non-genetic) to infection and trauma;
- nerve or muscle injury or irritation;
- hormonal changes.
184.108.40.206. Chronic pelvic pain and prolapse/Incontinence mesh
Continence and prolapse mesh implants were developed as simple flexible polypropylene plastic acting as a scaffold to treat stress urinary incontinence (SUI) and uterovaginal prolapse, respectively. They were deemed easy to insert, but no credence was given as to how safe they were, whether they could be removed should they cause complications, or what to do should they not be effective [169,170]. Most meshes took less than an hour to implant surgically and most patients were treated as day cases, allowing women to leave hospital quickly and get on with their lives. Therefore, rather than undergo complex traditional surgery, women were offered permanent mesh implants, particularly in the treatment of SUI where they were considered to be the gold standard [171,172]. However, over the last few years the insertion of mesh has come with significant ‘health and safety warnings’ [173,174].
For many, mesh was initially seen not just as an effective treatment but as a permanent one. Complications were not thought to be a significant issue and the figure of 1-3% was often quoted. However, we now know the complication rate was closer to 10% . They included chronic pain [176,177], as well as chronic infections , erosion into the surrounding organs including the vagina, urethra and bladder, as well as nerve and musculoskeletal damage affecting mobility [176,177,179,180]. All had a significant impact on the patients’ QoL.
Early recognition of possible mesh complications is very important. It is normal to wake up in some degree of discomfort after any surgery. However, if the pain after the operation is very severe and much more than expected after this type of surgery, it can be a sign that there was added trauma to the surrounding organs during the procedure. Most pain is often managed with analgesia, but some women might not fully respond to therapy. If the pain is difficult to treat and does not improve over time, it may become necessary to remove the mesh. Leaving a painful mesh in the pelvis, can lead to chronic pelvic pain. The precise mechanism is unknown but it is thought to be a ‘neuro-inflammatory’ process , as has been proposed in hernia mesh neuralgia. The impact of the mesh, regardless of site, appears to be similar.
220.127.116.11. Chronic post-surgical pain
Chronic post-surgical pain
Chronic pain may develop following surgical procedures and has a significant impact on the individual. The ICD-11 has recently classified chronic post-surgical pain (CPSP) as a chronic pain condition. The definition of CPSP is chronic pain that develops or increases in intensity after a surgical procedure and persists beyond the
healing process, i.e., at least three months after the surgery .
Chronic post-surgical pain may occur in a significant number of patients, and is more prevalent following some operations rather than others. Procedures with a higher risk of CPSP include limb amputation (30-85%), thoracotomy (5-65%) and mastectomy (11-57%) .
Risk factors for CPSP include a number of pre-, peri- and post-operative factors. Younger age, female gender, chronic pain pre-operatively elsewhere, higher number of previous operations, use of opioids and a higher post-operative pain score have been found to be associated with a higher risk of CPSP in a prospective cohort of patients undergoing laparoscopy and laparotomies. Older age, malignant indication for surgery, a higher pre-operative mental health score and the use of epidural analgesia in addition to general anaesthesia were protective [185,186].
There are a number of procedures specific to the abdomen and pelvis that are associated with an increased risk of chronic pain post-surgery, including bariatric procedures, inguinal hernia repair, vasectomy, hysterectomy and caesarean section. Adhesions are a common cause of chronic abdominal pain but despite this, a SR identified only low level evidence to help guide management of affected individuals .
The estimated prevalence of CPSP following bariatric surgery is 30% . In affected individuals careful assessment that may include laparoscopy could identify a treatable cause (such as adhesions, mesenteric defect or cholecystitis) and lead to a significant reduction in post-operative pain .
Inguinal hernia repair can lead to CPSP in up to 10% of patients at six months  and may present with groin and/or scrotal pain.
The incidence of post-surgical pain following hysterectomy is difficult to determine as pain is a common indication for the operation. When defined as CPSP, rates are estimated at 28-30% [190,191]. Careful case selection and management of patient expectation is therefore important.
The frequency of caesarean section has increased over time. A meta-analysis has shown a significant incidence of CPSP both at three months and at more than twelve months (15% and 11% respectively) , therefore careful counselling is needed in non-emergency cases.
18.104.22.168. Associated conditions in pelvic pain syndromes
Spinal pathology and any pathology along the course of the nerve involved may result in neuropathic pain in the distribution of these nerves. Neoplastic disease, infection, trauma, surgical incisions and post-operative scarring may result in nerve injury .
Pudendal neuralgia is the most often mentioned form of nerve damage in the literature. Anatomical variations may pre-dispose the patient to developing pudendal neuralgia over time or with repeated low-grade trauma (such as sitting for prolonged periods of time or cycling) [194,195].
The pudendal nerve may be damaged at the level of:
1.The piriformis muscle. For example, as part of a piriformis syndrome: in some cases, the nerve may pass through the muscle and hence be trapped; or in other cases, muscle hypertrophy or spasm is implicated.
The clinical presentation depends on different factors. There is a wide age range, as one would expect, with a condition that has so many potential causes. It is suggested that, the younger the patient, the better the prognosis. Essentially, the sooner the diagnosis is made, as with any compression nerve injury, the better the prognosis, and older patients may have a more protracted problem [196-198]. Six out of ten cases are observed in women. Some special situations can be listed:
- In orthopaedic hip surgery, pressure from the positioning of the patient, where the perineum is placed hard against the brace, can result in pudendal nerve damage [199,200]. The surgery itself may also directly damage the nerve. Pelvic surgery such as sacrospinous fixation is clearly associated with pudendal nerve damage in some cases [201,202]. In many types of surgery, including colorectal, urological and gynaecological, pudendal nerve injury may be implicated.
- Fractures of the sacrum or pelvis may result in pudendal nerve/root damage and pain. Falls and trauma to the gluteal region may also produce pudendal nerve damage if associated with significant tissue injury or prolonged pressure.
- Tumours in the pre-sacral space must be considered. Tumours invading the pudendal nerve may occur and there may also be damage from surgery for pelvic cancer .
- The pudendal neuralgia of birth trauma is thought to resolve in most cases over a period of months. However, rarely, it appears to continue as painful neuropathy. Multiple pregnancies and births may predispose to stretch neuropathy in later life. This is more difficult to be certain about .
- Child birth and repeated abdominal straining associated with chronic constipation  are thought to pre-dispose elderly women to post-menopausal pelvic floor descent and stretching of the pudendal nerve with associated pain. Changes in the hormone status may also be a factor. In Urogenital Pain Management Centres, the commonest associations with pudendal neuralgia appear to be: history of pelvic surgery; prolonged sitting (especially young men working with computer technology); and postmenopausal older women.
Chronic pelvic pain is a clinical condition that results from complex interactions of physiological and psychological factors and has a direct impact on the social, personal and professional lives of men and women.
Chronic pain as well as its treatment can impair our ability to express sexuality. In an England study, 73% of patients with any chronic pain had some degree of sexual problems as a result of the pain . These problems can occur because of several factors. Psychological factors like decrease in self-esteem, depression and anxiety can contribute to loss of libido. Physiological factors like fatigue, nausea and pain itself can cause sexual dysfunction. Pain medications (opioids, and the selective serotonin re-uptake inhibitors [SSRIs]) can also decrease libido  and delay ejaculation. The number of studies on the effects of CPPPS on sexual function is limited. Sexual dysfunction is often ignored because of a lack of standardised measurements. At present, the most commonly used tool is the IIEF questionnaire .
The presence of pelvic pain may increase the risk for ED independent of age . On the other hand, cross-sectional data suggest no improvement of lower urinary tract symptoms (LUTS) by an increased frequency of ejaculation . Although mental distress and impaired QoL related to illness could contribute to sexual dysfunction observed in patients with PPPS, the presence of erectile and ejaculatory disorders is more frequently related to symptoms suggestive of a more severe inflammatory condition . These arguments are important for the understanding of the close relationship between CPPPS symptoms, disturbed sexuality, impact on QoL, and psychological implications including depression and more failure anticipation thoughts [107-109,208-210]. Sexual dysfunction heightens anger, frustration and depression, all of which place a strain on the patients’ relationships. The female partners of men with sexual dysfunction and depression often present with similar symptoms including pain upon intercourse and depressive symptoms. Men with CPPPS have reported a high frequency of sexual relationship dissolution and psychological symptoms, such as depression and suicidal thinking [107,211]. Primary Prostate Pain Syndrome patients reported substantial sexual and relationship problems [107,211]. On the other hand, it was found that men with PPPS did not report significantly decreased sexual satisfaction compared to controls . There is consensus that therapeutic strategies reducing symptoms of pelvic pain are of relevance in relation to changes in sexual function. Also intimacy and having sex can yield positive experiences that will reduce the pain. The CNS plays an important role in this mechanism.
Chronic pelvic pain leads to substantial impairment in QoL and several sexual dysfunctions [119,213-215]. It seems reasonable to expect that pain, extreme fatigue, depressive mood and pain drugs will affect women’s sexuality. Women with CPPPS reported significantly more pain, depression, and anxiety symptoms and were physically more impaired than women in the control group. In comparison with controls, women with CPPPS reported significantly more sexual avoidance behaviour, non-sensuality, and complaints of “vaginismus” . Patients with CPPPS reported more sexual problems than women with any other type of chronic pain problem . The quality of intimate relationships is closely connected with sexual function . Satisfaction with sexual relationships appears to be associated with higher marital functioning . In addition sexual dissatisfaction is related to sexual dysfunction. When one partner suffers from chronic pain, the ability of both partners to cope with the pain and the extent to which partners are supportive of the chronic pain sufferer have been found to be a predictor of sexual functioning .
Approximately two-thirds of patients in another study reported reduced frequency in their sexual relations as a result of CPPPS . One study demonstrated that CPPPS patients reported worse sexual function with regard to desire, arousal, lubrication, orgasm, satisfaction, and more frequent and severe pain with vaginal penetration than women without CPPPS . In an interview with 50 chronic pain sufferers and their spouses, 78% of the pain sufferers and 84% of partners described deterioration, including cessation of their sex life . In a study in patients with back pain, half reported decreased frequency of sex since the onset of chronic pain . The Female Sexual Function Index (FSFI) has been developed as a brief, multi-dimensional self-report instrument for assessing the key dimensions of sexual function in women, which includes desire, subjective arousal, lubrication, orgasm, satisfaction, and pain. Using the FSFI, women with CPPPS reported worse sexual function in all subscales and total score than women without CPPPS. The largest differences between women with CPPPS and without CPPPS, were seen for the domains of pain and arousal. The total score and the subscales of the FSFI had high levels of internal consistency and test-retest reliability when assessed in a sample of women with CPPPS. The FSFI also showed good ability to discriminate between women with and without CPPPS .
Myalgia is too often overlooked as a form of chronic pelvic pain. The pelvic floor and adjacent muscles are used in an abnormal way. Studies in the field of chronic prostatitis support the idea that patients with CPPPS have more muscle spasm and increased muscle tone and report pain when the pelvic floor muscles are palpated . Learning pelvic floor muscle relaxation can diminish spasm and pain . Repeated or chronic muscular overload can activate trigger points in the pelvic floor muscles. A report from the Chronic Prostatitis Cohort Study showed that 51% of patients with prostatitis and only 7% of controls had any muscle tenderness. Tenderness in the pelvic floor muscles was only found in the CPPPS group .
The first ideas about the neurological aspects of the pelvic floor muscles in relation to chronic pelvic pain were published in 1999. The possibility of CNS changes in the regulation of pelvic floor function was suggested as a mechanism for development of CPPPS. Of the patients presenting with pelvic pain, 88% had poor to absent pelvic floor muscle function . Animal studies on the role of neurogenic inflammation have also elucidated some important phenomena. Irritation of the prostate, bladder and pelvic floor muscles results in expression of C-fos-positive cells in the CNS. There appears to be convergence of afferent information onto central pathways. Once the central changes have become established, they become independent of the peripheral input that initiated them .
Repeated or chronic muscular overload can activate trigger points in the muscle. Trigger points are defined as hyper-irritable spots within a taut band. Other criteria for trigger points are recognition of the pain as ‘familiar’, and pain on stretching the muscle. Apart from pain, trigger points prevent full lengthening of the muscle, thereby restricting the range of movement. Pain as a result of these trigger points is aggravated by specific movements and alleviated by certain positions. Positions and movements in which the shortened muscle is stretched are painful. Patients know which activities and postures influence pain. Trigger points can be located within the pelvic floor muscles and in adjacent muscles such as the abdominal, gluteal and iliopsoas muscles. Pain is aggravated by pressure on the trigger point (e.g., pain related to sexual intercourse). Pain also worsens after sustained or repeated contractions of pelvic floor muscles (e.g., pain related to voiding or defecation).
3.3. Abdominal aspects of pelvic pain
Epidemiological data on IBS and CPPPS are scarce . Chronic Pelvic Pain has been shown to be one of the most common functional disorders in women of reproductive age. The monthly incidence rate of CPPPS published by Zondervan et al. was 1.58/1000 .
Using a vague definition of continuous or episodic pain situated below the umbilicus over six months, one study reported that CPPPS was one of the most common diagnoses in primary care units in Great Britain . The monthly prevalence rate of CPPPS in this study was 21.5/1,000, with an annual prevalence of 38.3/1,000. The prevalence rates increase significantly with older age and vary significantly between regions in the UK. The overall prevalence of anorectal pain in a sample of USA householders was 6.6% and was more common in women . Irritable bowel syndrome is associated with common gynaecologic problems (endometriosis, dyspareunia, and dysmenorrhoea) . Fifty per cent of women who presented with abdominal pain to the gynaecologic clinic or were scheduled for laparoscopy due to CPPPS had symptoms of IBS . In a survey from Olmsted county, 20% of women reported CPPPS and 40% of those met the criteria for IBS . This overlap of CPPPS and IBS was associated with an increased incidence of somatisation. Not gynaecological surgical procedures but only psychosocial variables predict pain development without a different incidence of IBS in a prospective and controlled study . Clinical features of pelvic floor dysfunction, gynaecological and psychological features, are related to disordered anorectal function in IBS patients, but do not predict physiological anorectal testing.
3.3.3. Influence on Quality of Life
There is little known on health related quality of life (HRQoL) in patients with CPPPS. There is a need to develop validated disease specific HRQoL instruments for CPPPS in addition to sound measurement properties. More data are available in patients with IBS treated at referral centres who have comparable HRQoL scores as patients with other common disorders such as diabetes, end-stage renal disease, and inflammatory bowel disease . Sub-groups of IBS with predominance of diarrhoea or constipation show no difference in HRQoL. Multi-variate analysis shows that HRQoL in patients with IBS is affected by sex and psychological conditions.
Costs combine direct health-care costs and societal costs (productivity loss) such as under-performance and absenteeism from work. The annual costs to society can be calculated by using the average population earnings. In Germany direct care costs are estimated at €791 and societal costs €995 per patient with IBS per year which may be comparable to patients with CPPPS .
3.3.5. Risk factors & underlying causes
Risk factors are covered in Section 3.1.5.
3.4. Summary of evidence and recommendations: CPPPS and mechanisms
Summary of evidence
CPPPS mechanisms are well defined and involve mechanisms of neuroplasticity and neuropathic pain.
The mechanisms of neuroplasticity and neuropathic pain result in increased perception of afferent stimuli which may produce abnormal sensations as well as pain.
End-organ function can also be altered by the mechanisms of neuroplasticity so that symptoms of function can also occur.
The diagnosis of a CPPPS as a pain syndrome is essential as it encourages a holistic approach to management with multi-specialty and multi-disciplinary care.
All of those involved in the management of chronic pelvic pain should have knowledge of peripheral and central pain mechanisms.
The early assessment of patients with chronic pelvic pain should involve investigations aimed at excluding disease-associated pelvic pain.
Assess functional, emotional, behavioural, sexual and other quality of life issues, such as effect on work and socialisation, early in patients with chronic pelvic pain and address these issues as well as the pain.
Build up relations with colleagues so as to be able to manage CPPPS comprehensively in a multi-specialty and multi-disciplinary environment with consideration of all their symptoms.