In Category II, patients are usually presented with recurrent lower urinary tract infections. The most common organisms are the Enterobacteriaceae family of gram-negative bacteria, which originate in the gastrointestinal flora. Escherichia coli are identified in 65–80 % of infections [23, 24]. Besides Enterobacteriaceae, other microorganisms such as Gram-Positive Enterococci, anaerobic bacteria, Staphylococcus saprophyticus, and Staphylococcus aureus, have been described [25, 26]. The nidus of infection is the prostate gland [27]. Patients may be relatively asymptomatic between acute episodes, or they may present with a long history of a CPPS [28].

Pain is the main symptom in category III, accompanied by variable voiding and sexual dysfunction symptoms. The clinical presentation of category IIIA is indistinguishable from category IIIB. The pain may be localized to suprapubic area, penis (referred to the tip of the penile urethra), perineum, testes, groin or low back. Some patients complain of painful ejaculation [29, 30]. Many patients have storage and voiding symptoms such as urinary urgency, increased frequency, nocturia, dysuria, hesitancy, diminished urinary stream, and poor interrupted flow.

Records of 1563 category III patients from four databases from Canada, Germany, Italy, and the United States showed that the most prevalent location of pain was the Perineum (63 %) followed by testicular pain (58 %), pain in the pubic area (42 %) and penis (32 %); reports of pain during ejaculation and voiding were 45 % and 43 %, respectively [31].

The neurologic and genitourinary physical examination is usually normal, except for some patients who present tender prostatic and paraprostatic tissues on digital rectal examination. Sexual disturbances such as erectile dysfunction and premature ejaculation are common complaints as well [2, 32–34]. The quality of life of these patients is usually severely impaired [35, 36]. Depression, emotional distress, and anxiety are common characteristics of patients with CPPS [37, 38].

In CP/CPPS there are no objective tools that can evaluate outcomes. Therefore, it is very important to have a validated and a reproducible instrument to measure the symptoms and quality of life of patients for use in research protocols as well as clinical practice. The NIH (National Institute of health) Chronic Prostatitis Collaborative Research Network (CPCRN) developed the NIH-CPSI (chronic prostatitis symptoms index) which is currently the most acceptable validated tool for symptom assessment is CP/CPPS patients [39]. The index consists of nine items that address pain (location, severity, and frequency), urinary function (incomplete emptying, frequency, and urgency) and impact on the quality of life (effect of symptoms on daily activities). The NIH-CPSI has shown validity in clinical trials [40] and has now been accepted by the international prostatitis research community as an accepted outcome measure [41].

The etiology for chronic bacterial prostatitis (category II) is unknown. The histological findings are nonspecific. Usually, the inflammatory reaction is less marked and more focal than that seen in cases of acute bacterial prostatitis. Infiltration by macrophages and plasma cells is prominent within and around the acini, along with focal invasion of lymphocytes. Because these findings are very common in patients without evidence on prostatitis, they are not diagnostic [42].

Transrectal prostatic ultrasonography often detects prostatic calculi of variable size and number in adult prostates, with an incidence of about 75–100 % [43]. These stones are typically small and tend to occur in clusters. In patients with chronic bacterial prostatitis, the stones are usually multiple and large. These stones can become infected and may serve as a source of bacterial persistence and relapsing infections [44]. The clinical features of men who have chronic bacterial prostatitis with or without stones are indistinguishable. Potential risk factors for prostate bacterial colonization include: unprotected penetrative ano-rectal intercourse, urinary tract infection, phimosis, acute epididymitis, indwelling urethral catheters, transurethral surgery, and intraprostatic ductal reflux [45]. Crystallographic analysis of prostatic stones indicates that certain calculi are composed of constituents commonly found in the urine but foreign to prostatic secretions. This observation suggests that intraprostatic reflux of urine is important in the formation of some prostatic stones [46].

Studies have excluded infectious agents as causative agents including fungi, viruses, trichomonads, bacteria, Mycoplasma, and Ureaplasma species [47, 48]. The most controversial supposed agent in CPPS is Chlamydia trachomatis. It is plausible that this organism has an etiologic role in prostatitis since it is the most common causative agent of acute epididymitis and urethritis in young men [49]. However, many studies showed that C. trachomatis appears to play a minor role, if any, in the etiology of CPPS. These studies used cultural and serologic tests of prostatic fluids, immunofluorescent tests of the serum, urethra, and prostate [48, 50–52].

Dysfunctional voiding and functional bladder outlet obstruction is another possible etiology for CPPS. Incomplete funneling of the bladder neck as well as vesicourethral dyssynergic patterns were demonstrated on videourodynamic of many patients with CPPS [53–55]. High pressure voiding may lead to autonomic overstimulation of the perineal-pelvic neural system with subsequent development of a chronic neuropathic pain. However, since painful voiding is quite common in CPPS patients—it is plausible that the functional obstruction is the outcome and not the cause of CPPS.

Intraprostatic reflux due to high pressure voiding has been hypothesized as a central etiologic mechanisms involved in the pathogenesis of CPPS as well. High levels of urate and creatinine were noted in EPS. It was postulated that this may be caused by urine reflux into the prostatic ducts [56]. The inflammatory process in the prostate may be due to chemically induced inflammation, secondary to noxious substances in the urine that have refluxed into the prostatic duct. Another study showed that carbon particles instilled into the bladder can be found in the EPS macrophages and prostatic acini and ductal system after surgery in men with CPPS [57].

Prostatic calcifications are common in patients with CPPS as well [58]. It has been shown that patients with CPPS or chronic bacterial prostatitis have significantly higher prostate tissue pressure than controls, measurable with transperineally inserted pressure transducers [59]. It was postulated that inflammation resulting from chemical, bacterial, or immunologic stimulation is the main cause for such high pressure and maybe for the formation of intraprostatic stones.

There is some evidence that CPPS may be secondary to immunologically mediated inflammation, due to some unknown antigen, or perhaps even related to autoimmunity. Elevated levels of cytokines (IL-1, IL-8, IL-10, and tumor necrosis factor) in the seminal plasma and prostatic secretions have been detected in men with CPPS compared with normal individuals, suggesting an active inflammatory process in the male genital tract [60–62].

This inflammatory reaction may be mediated by an adaptive immune response directed against genital tract antigens [63]. PSA has been suggested as the self-antigen [64]. Fibrinogen and complement C3 have been identified in prostatic biopsy specimens from patients with CPPS [65]. High levels of nonspecific IgA and IgM antibodies were demonstrated in prostatic fluid of patients with CPPS [52].

Psychological factors may play a role in the pathophysiology of CPPS as well. A case control study confirmed that depression and panic disorders are significantly more common in men and women with chronic pelvic pain conditions than in control subjects [66]. It has been shown that hypochondriasis, depression, somatization, anxiety, and hysteria are more common in CPPS patients than control [67–69]. Depressive symptoms, pain intensity, pain catastrophizing, and pain-contingent resting significantly predict a poorer quality of life in patients with CPPS regardless of age and urinary status [70, 71]. This indicates that negative cognitive assessment of the pain experience may be a primary target for psychosocial interventions.

Dysfunctional hypothalamic-pituitary-adrenal axis function was demonstrated in men with chronic pelvic pain syndrome, reflected by insignificant increases in awakening cortisol levels [67]. Comparing to age-matched asymptomatic healthy controls, CPPS patients had significantly higher levels of progesterone, androstenedione and testosterone and significantly lower levels of corticosterone, aldosterone and 11-deoxycortisol. Interestingly, the National Institutes of Health-Chronic Prostatitis Symptom Index total and pain domain scores correlated positively with 17-hydroxyprogesterone and aldosterone (P < 0.001) and negatively with cortisol (P < 0.001) concentrations [68]. These findings provide further insights into the biologic basis of CP/CPPS suggesting that the hormonal imbalance is influenced by symptom severity.

At present, antimicrobial agents are the treatment of choice for chronic bacterial prostatitis (category II). Numerous antibiotics have been tested including erythromycin, minocycline, doxycycline, and cephalexin, in most cases with quite disappointing results. Cure rates of 30–40 % with long-term TMP-SMX (4–16 weeks) have been documented [72, 73]. Direct transperineal injection of antibiotics directly into the caudal prostate showed outstanding success in 24 selected patients with refractory chronic bacterial prostatitis. Remission periods of at least 6 months were obtained in 70 % of these patients after one or two infiltrations. Seven patients had relapse after remission periods ranging from 13 months to 7 years [74]. Fluoroquinolones cover the spectrum of gram-positive and gram-negative bacteria and have been shown to penetrate into prostatic tissue in concentrations approaching or exceeding by several fold those in serum [75, 76]. In a comparative study, 4–6 weeks of norfloxacin was shown to be more effective than TMP-SMX for therapy of chronic bacterial prostatitis caused predominantly by E. coli [77].

Prolonged therapy (4–6 weeks) of ciprofloxacin appeared to eradicate E. coli prostatitis in 85 % of patients [78]. A prospective open-label study on 116 patients with chronic bacterial prostatitis showed that administering once daily 500 mg of levofloxacin for 28 days a clinical success rate (cured and improved patients) of 77, 66, and 62 % at 1 month, 3 months, and 6 months was achieved [79]. Lower rates of eradication have been associated with therapy given for shorter periods and with prostatitis caused by agents other than E. coli [80]. Chronic infections unresponsive to such treatment are generally managed by continuous, suppressive, low dose of TMP-SMX or nitrofurantoin; neither tends to produce bacterial resistance [81].

Theoretically, removal of the infected material, including potentially infected calculi may be effective in patients with either relapsing or refractory chronic bacterial prostatitis secondary to bacterial persistence within the prostate gland. Patients with prostatic calculi not controlled by medical therapy may be candidate for transurethral prostatectomy. In such circumstances, the procedure may be quite challenging, since the greatest foci of stones are located in the peripheral zone of the prostate [82]. There is no substantial proof in the literature as to the efficacy of prostate surgery in category II chronic prostatitis.

Up to 40 % of the patients with CPPS have symptomatic improvement with antibiotic therapy [25, 48, 83, 84]. Possible explanations for the positive effect of antibiotic on CPPS patients are: independent anti-inflammatory effect of some antibiotics, placebo effect and suppression of noncultured microorganisms. However, two recent randomized placebo-controlled studies which evaluated the efficacy of 6 weeks of levofloxacin [85] and ciprofloxacin [86] on antibiotic-naive patients with CPPS showed no significant difference between drugs and placebo.

Since many patients with CPPS show functional obstruction of the bladder neck and prostate, alpha-adrenergic blocking agents were considered as an important and efficient treatment for this syndrome [87–89]. However, more recent studies concluded that these drugs are no better than placebo [86, 90]. A multicenter, randomized, double-blind, placebo-controlled trial was conducted in order to assess the efficacy of alfuzosin in reducing symptoms in men with CPPS. 272 men were randomized to alfuzosin or placebo. The NIH-CPSI scores did not differ between the groups after 12 weeks of treatment [90].

A short course of anti-inflammatory agents is often helpful for exacerbation of pain and dysuria [91]. Oral corticosteroids showed no benefit over placebo in a randomized trial [92]. A modest improvement with rofecoxib (cyclooxygenase-2 inhibitor) was demonstrated in a placebo-controlled randomized trial [93].

Patients with tension myalgia of the pelvic floor respond best to treatment with muscle relaxants, alone or in combination with an alpha-adrenergic blocking agent [81]. A prospective double-blind crossover study comparing phenoxybenzamine, baclofen, and placebo in 27 patients with CPPS, showed symptomatic improvement in 37 % of the patients treated with baclofen compared with 8 % treated with placebo [94]. A double-blind comparative study between diazepam and minocycline in CPPS patients found no difference in symptom improvement [95].

Hormonal treatment with 5α-reductase inhibitors may reduce the prostatic glandular tissue and therefore improve voiding parameters, especially in patients with a BPH component. A randomized comparison between finasteride and placebo in patients with CCPS showed a significant improvement in the Prostatitis Symptom Severity Index and BPH symptom score. However, there was no difference in pain between the two groups [96]. A randomized placebo-controlled trial evaluated the efficacy of 6 months therapy with finasteride versus placebo [97]. The improvement in the NIH-CPSI and in subjective overall assessment was similar between groups.

A prospectively randomized study compared the efficacy of mepartricin (which lowers estrogen levels in the prostate) versus placebo in 26 patients with CPPS [98]. A significant decrease in the total NIH-CPSI score from 25.0 to 10.0 was demonstrated in the mepartricin group compared to reduction from 25.0 to 20.0 in the placebo group. Moreover, a statistically significant decrease was observed with regard to pain (from 11.0 to 4.0 and from 10.0 to 8.0, respectively).

At the first half of the twentieth century, prostatic massage was the principal treatment for prostatitis. However, during the years, this practice was abandoned by urologists due to lack of good evidential support. The benefit from prostatic massage is believed to be derived from a combination of several factors, including expression of prostatic secretions, relief of pelvic muscle spasm, physical disruption of any protective biofilm, improved circulation, and consequently improved antibiotic penetration [99, 100]. Repetitive prostatic massages (one to three times per week) combined with antibiotics was evaluated in patients suffering from chronic bacterial prostatitis (n = 52) and CPPS (n = 19). Overall, 40 % of this heterogeneous group had complete resolution of symptoms [101]. A more recent study showed no significant difference in response between patients treated with antibiotics alone and those treated with antibiotics and prostatic massage [102]. Despite prostatic massage having been practiced for a long time, there is a paucity of literature on this subject. There is not a single comparative study that has evaluated prostatic massage alone as a therapy for CPPS.In the absence of an ideal sham procedure to mimic prostatic massage, it may never be possible to eliminate the placebo effect, and thus the most robust evidence on this subject may continue to be elusive [100]. Frequent ejaculation may achieve the same function as prostatic massage [103].

It is believed that prolonged chronic tension, distention, or distortion in the muscle bands (e.g., in the perineum) may lead to painful trigger points that are responsible for pain in patients with chronic pelvic pain syndromes. Anderson et al. [104] documented relationships between trigger point sites and pain symptoms in 72 men with CPPS. Pain sensation at each anatomical site was reproduced by palpating at least 2 of 10 designated trigger points. Furthermore, 5 of 7 painful sites could be reproduced at least 50 % of the time (p < 0.05). The most prevalent pain sites were the penis in 90.3 % of men, the perineum in 77.8 % and the rectum in 70.8 %. Puborectalis/pubococcygeus and rectus abdominis trigger points reproduced penile pain more than 75 % of the time (p < 0.01). External oblique muscle palpation elicited suprapubic, testicular, and groin pain in at least 80 % of the patients at the respective pain sites (p < 0.01). This report showed a relationship between myofascial trigger points and reported painful sites in men with CPPS. Manual release therapy of these trigger points may be an effective therapeutic approach in some patients [105]. Combining physical therapy and biofeedback may improve symptoms as well. A study on 31 males with CPPS showed a reduction of the CPSI from 23.6 (range 11–34) to 11.4 (range 1–25, p < 0.001) after biofeedback physical therapy [106].

Phytotherapy for CPPS patients is another potential treatment for CPPS patients. Some plant extracts have been shown to have alpha-adrenergic blockade activity, effects on detrusor contractility, anti-inflammatory activity, and 5-alpha reductase properties. A prospective, randomized, double-blind, placebo-controlled phase 3 study compared a pollen extract (Cernilton) to placebo in men with CPPS [107]. 139 men were randomly allocated to the pollen extract (n = 70) or placebo (n = 69). The individual domains pain (p = 0.0086) and quality of life (QoL; p = 0.0250) as well as the total NIH-CPSI score (p = 0.0126) were significantly improved after 12 weeks of treatment with pollen extract compared to placebo. The bioflavonoid Quercetin was shown to be superior to placebo in a small prospective randomized, double-blind, placebo-controlled trial [108]. Patients taking placebo had a mean improvement in NIH symptom score from 20.2 to 18.8 (not significant), while those taking the bioflavonoid had a mean improvement from 21.0 to 13.1 (P = 0.003). Twenty percent of patients taking placebo and 67 % of patients taking the bioflavonoid had an improvement of symptoms of at least 25 %. It has been shown that Serona repens (saw palmetto berry) has antiandrogenic actions and anti-inflammatory activity in prostatic epithelial cells [109]. Moreover, Serona repens has been shown to reduce clinical progression rates in men with mild symptoms of bladder outlet obstruction. It also led to improvements in urinary symptoms, QOL scores, and urinary flow rates [110]. However, no published randomized placebo-controlled study has compared the efficacy of Serona repens to placebo in CPPS patients yet.

One of the theories regarding the pathophysiology of symptoms in CPPS is neuropathic pain [111]. Therefore, there is a rational to treat these patients with Neuromodulators. A randomized, double-blind, placebo-controlled trial evaluated the efficacy of pregabalin in patients suffering from CPPS [112]. Compared with the placebo group, men assigned to receive pregabalin had a higher Global Response Assessment rate (31.2 and 18.9 %; P = 0.02), and showed improvement in total McGill Pain Questionnaire score (P = 0.01). However, there was no difference between groups in the NIH-CPSI total score, which was the primary end-point. Antidepressants (e.g., amitriptyline), which are well established in the management of other chronic pain syndromes, are sometimes used with some success, but have not been formally evaluated in CPPS.

Electrical Neuromodulation techniques used for chronic pelvic pain conditions include SNS (sacral nerve stimulation), PTNS (percutaneous tibial nerve stimulation) and pudendal nerve stimulation. Only SNS and PTNS are currently approved by the US Food and Drug Administration for the treatment of urinary symptoms and none of these methods are acknowledged as standard therapies for treating chronic pelvic pain syndromes. Although research on PTNS method for male CPPS is sparse, Kabay et al. reported on a trial of 89 men with the diagnosis of medically refractory NIH Category IIIB CPPS who were randomly assigned to receive either PTNS or sham treatment. The PTNS group reported a significant improvement in urinary symptom and pain scores, yet follow-up after the 12-week treatment period was not reported [113, 114]. The most common technique of SNS places a multipolar lead through S3 sacral foramen to stimulate the nerve root. In recent years, several reports have been published regarding the use of SNS to treat IC/BPS symptoms, most commonly using Interstim (Medtronic, Minneapolis, MN). Most of the literature pertaining to SNS presents case series including different types of chronic pelvic pain [113]. Zabihi et al. [115] studied the use of bilateral sacral electrodes and reported >50 % pain improvement in 10 out of 23 patients with debilitating pelvic pain (IC/BPS and male CPPS) who had bilateral sacral electrodes implanted. Currently, there is a lack of studies specifically utilizing SNS and PTNS in men with CP/CPPS. Conclusions of the existing literature must be carefully considered because of paucity of data and the limitations of small studies.

Other potential treatments that may ease symptoms of CPPS patients include: anticholinergic drugs to control bladder storage symptoms (such as urinary urgency and frequency), avoiding irritating foods and beverages (such as caffeine, spicy dishes, alcohol, citrus, sparkling drinks), acupuncture and anxiolytic drugs for patients with significant emotional distress [116–118].

Surgical interventions may be offered to patients who have been refractory to other treatments. Some anecdotal experiences exist for radical prostatectomy and transurethral resection of the prostate; however, these have been largely abandoned due to lack of reliable data to support their use, the potential for significant morbidity, and questionable benefit [119].

Minimally invasive treatments that were evaluated only in small pilot studies include: sacral magnetic stimulation [120], intraprostatic injection of botulinum toxin [121, 122], percutaneous posterior Tibial nerve stimulation [114], and transurethral microwave hyperthermia [123]. Treatments proven to be ineffective include balloon dilatation [124] and transurethral needle ablation [125].

Transurethral microwave thermotherapy (TUMT) was found to be effective in a randomized, double-blind, sham-controlled study. Seventy percent of the patients showed greater than 50 % improvement in symptoms [126]. A more recent study [127] demonstrated similar results, with 63 % of patients maintaining at least a 50 % improvement of pain symptoms 12 months after the procedure.

The use of extracorporeal shockwave therapy (ESWT) has been evaluated for the treatment of CP/CPPS. A placebo-controlled, prospective, randomized, double-blind study of 60 patients noted a significant improvement of pain, quality of life, and voiding symptoms when compared to placebo over a 12-week follow-up period. This procedure was performed without anesthesia or any noted significant side effects [124]. This study provides level-1 evidence for a potentially promising new therapy for CP/CPPS, but further evaluation of ESWT appears to be warranted.

Although IC typically occurs less frequently in men than in women, contemporary series have suggested that male IC is much more common than was previously thought [145]. CP/CPPS in men may masquerade as IC/PBS, or vice versa. Both syndromes have rather similar and nonspecific symptoms and are actually diagnosed per exclusion. Probably, many men who are diagnosed as suffering from CP/CPPS actually have IC/PBS [146, 147]. The etiology of these enigmatic syndromes is unknown. However, the pathogenic mechanisms are theorized to be similar in men [148–150]. Undoubtedly, the symptoms of IC/PBS and CP/CPPS overlap to some extent.

Interestingly, men with CP/CPPS diagnoses have findings on cystoscopic [151], urodynamic [142], and potassium sensitivity testing [152] which are very similar to those of patients with IC. Miller et al. [147] observed petechial hemorrhages (glomerulations) in the bladder during hydrodistention under general anesthesia in 12 out of 20 men with CPPS. A study on 30 men who were initially thought to have CPPS and were refractory to treatment revealed the typical appearance of glomerulations after hydrodistention. Cold-cup bladder biopsies revealed increased number of mast cells in the mucosa in all patients [81]. Therefore, the diagnosis of IC/PBS should be considered in CPPS patients that are refractory to treatment.

Interstitial cystitis/painful bladder syndrome (IC/PBS) is discussed in details in a different chapter of this book.

Acute scrotal pain is usually a result of a well-defined condition such as trauma, torsion of the testis or its appendages, epididymitis, renal colic (referral pain), etc. However, the etiology of chronic testicular pain (orchialgia or orchidynia) is generally ambiguous and the management is often very challenging. It can be disabling and for many patients it is associated with anxiety about cancer. The desired goal of treatment is return to routine activity without significant use of analgesics.

Chronic testicular pain (CSP) was originally defined as intermittent or constant testicular pain for 3 months or longer which significantly interferes with daily activities of the patient so as to prompt him to seek medical attention [153]. The testis and epididymis have a common neuronal supply which can render it difficult to clinically distinguish the main site of pain [154]. Moreover, the majority of epididymectomy and orchiectomy specimens failed to show any pathological abnormalities [153, 155, 156]. Therefore, the definition of CSP was extended by Nickel et al. and included the testis, epididymis, and scrotum [157]. Thus, the terms chronic epididymitis, chronic orchialgia, and CSP are basically the same syndrome of chronic pain.