Chronic prostatitis/chronic pelvic pain syndrome

Chronic nonbacterial prostatitis
Classification and external resources
Specialty	urology
ICD-10	N41.1
ICD-9-CM	601.1
DiseasesDB	10801
MedlinePlus	000524
eMedicine	article/437745
MeSH	D011472

Chronic nonbacterial prostatitis or chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a pelvic pain condition in men, and should be distinguished from other forms of prostatitis such as chronic bacterial prostatitis and acute bacterial prostatitis.^[1][2] This condition was formerly known as prostatodynia (painful prostate).

Signs and symptoms

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is characterized by pelvic or perineal pain without evidence of urinary tract infection,^[3] lasting longer than 3 months,^[4] as the key symptom. Symptoms may wax and wane. Pain can range from mild to debilitating. Pain may radiate to the back and rectum, making sitting uncomfortable. Pain can be present in the perineum, testicles, tip of penis, pubic or bladder area.^[5] Dysuria, arthralgia, myalgia, unexplained fatigue, abdominal pain, constant burning pain in the penis, and frequency may all be present. Frequent urination and increased urgency may suggest interstitial cystitis (inflammation centred in bladder rather than prostate). Post-ejaculatory pain, mediated by nerves and muscles, is a hallmark of the condition,^[6] and serves to distinguish CP/CPPS patients from men with BPH or normal men. Some patients report low libido, sexual dysfunction and erectile difficulties.

Cause

Nerves, stress and hormones

The symptoms of CP/CPPS appear to result from an interplay between psychological factors and dysfunction in the immune, neurological and endocrine systems.^[7]

Theories behind the disease include stress-driven hypothalamic-pituitary-adrenal axis dysfunction and adrenocortical hormone (endocrine) abnormalities,^[8][9] neurogenic inflammation,^[10][11][12] and myofascial pain syndrome.^[13][14] In the latter two categories, dysregulation of the local nervous system due to past trauma, infection or an anxious disposition and chronic albeit unconscious pelvic tensing lead to inflammation that is mediated by substances released by nerve cells (such as substance P). The prostate (and other areas of the genitourinary tract: bladder, urethra, testicles) can become inflamed by the action of the chronically activated pelvic nerves on the mast cells at the end of the nerve pathways. Similar stress-induced genitourinary inflammation has been shown experimentally in other mammals.^[15] However, there is no correlation between inflammation on histological examination of the prostate and the National Institutes of Health Chronic Prostatitis Symptom Index.^[16]

The bacterial infection theory that for so long had held sway in this field was shown to be unimportant in a 2003 study from the University of Washington team led by Dr Lee and Professor Richard Berger. The study found that one third of both normal men and patients had equal counts of similar bacteria colonizing their prostates.^[17] This view was endorsed by Dr Anthony Schaeffer, Professor and Chairman of the Department of Urology at Northwestern University, in a 2003 editorial of The Journal of Urology, in which he stated that "...these data suggest that bacteria do not have a significant role in the development of the chronic pelvic pain syndrome",^[18] and a year later with his colleagues he published studies showing that antibiotics are essentially useless for CP/CPPS.^[19][20] Since the publication of these studies, the research focus has shifted from infection to neuromuscular, behavioral, psychological, and genetic etiologies for UCPPS (CP/CPPS and IC/PBS), where the interplay between the lower urinary tract and other physiological systems is stressed.^[21] UCPPS is now studied as a systemic disorder.^[21] In support of this approach, a 2005 study showed that stress is correlated to Cat III prostatitis.^[22]

Overlap with BPS/IC

Some researchers have suggested that CPPS is a form of bladder pain syndrome/interstitial cystitis (BPS/IC). In 2007 the NIDDK began to group IC/PBS and CP/CPPS under the umbrella term Urologic Chronic Pelvic Pain Syndromes (UCPPS). Therapies shown to be effective in treating IC/PBS, such as quercetin,^[23] have also shown some efficacy in CP/CPPS.^[24] Recent research has focused on genomic and proteomic aspects of the related conditions.^[25]

Patients may experience pain with bladder filling, which is also a typical sign of IC.^[26]

Climate

The ambient temperature appears to play a role as cold is frequently reported as causing symptom aggravation and heat is often reported to be ameliorating.^[27] It appears that cold is one of the factors that can trigger a process resulting in CP/CPPS.^[28] Cold also causes aggravation of symptoms and can initiate a relapse.^[28][29] A survey showed that the occurrence of prostatitis symptoms in men living in northern Finland —a cold climate—is higher than that reported in other parts of the world. This could be partly caused by the cold climate.^[30]

Food allergies

Anecdotal evidence suggests that food allergies and intolerances may have a role in exacerbating CP/CPPS, perhaps through mast cell mediated mechanisms. There is also some evidence of an association between urologic pain syndromes, such as IC/BPS and CP/CPPS, with non-celiac gluten sensitivity in some patients.^[31][32][33] Patients may therefore find an elimination diet helpful in lessening symptoms by identifying problem foods. Studies are lacking in this area.

Diagnosis

There are no definitive diagnostic tests for CP/CPPS. This is a poorly understood disorder, even though it accounts for 90–95% of prostatitis diagnoses.^[34] It is found in men of any age, with the peak incidence in men aged 35–45 years.^[35] CP/CPPS may be inflammatory (Category Ⅲa) or non-inflammatory (Category Ⅲb), based on levels of pus cells in expressed prostatic secretions (EPS), but these subcategories are of limited use clinically. In the inflammatory form, urine, semen, and other fluids from the prostate contain pus cells (dead white blood cells or WBCs), whereas in the non-inflammatory form no pus cells are present. Recent studies have questioned the distinction between categories Ⅲa and Ⅲb, since both categories show evidence of inflammation if pus cells are ignored and other more subtle signs of inflammation, like cytokines, are measured.^[36]

In 2006, Chinese researchers found that men with categories Ⅲa and Ⅲb both had significantly and similarly raised levels of anti-inflammatory cytokine TGFβ1 and pro-inflammatory cytokine IFN-γ in their EPS when compared with controls; therefore measurement of these cytokines could be used to diagnose category Ⅲ prostatitis.^[37] A 2010 study found that nerve growth factor could also be used as a biomarker of the condition.^[38]

For CP/CPPS patients, analysis of urine and expressed prostatic secretions for leukocytes is debatable, especially due to the fact that the differentiation between patients with inflammatory and non-inflammatory subgroups of CP/CPPS is not useful.^[39] Serum PSA tests, routine imaging of the prostate, and tests for Chlamydia trachomatis and Ureaplasma provide no benefit for the patient.^[39]

Extraprostatic abdominal/pelvic tenderness is present in >50% of patients with chronic pelvic pain syndrome but only 7% of controls.^[40] Healthy men have slightly more bacteria in their semen than men with CPPS.^[41] The high prevalence of WBCs and positive bacterial cultures in the asymptomatic control population raises questions about the clinical usefulness of the standard 4-glass test as a diagnostic tool in men with CP/CPPS.^[41] The use of the four-glass test by American urologists is now rare, with only 4% using it regularly.^[42]

Men with CP/CPPS are more likely than the general population to suffer from Chronic Fatigue Syndrome (CFS),^[43] and Irritable Bowel Syndrome (IBS).

Experimental tests that could be useful in the future include tests to measure semen and prostate fluid cytokine levels. Various studies have shown increases in markers for inflammation such as elevated levels of cytokines,^[44] myeloperoxidase,^[45] and chemokines.^[46][47]

Differential diagnosis

Some conditions have similar symptoms to chronic prostatitis: Bladder neck hypertrophy and urethral stricture may both cause similar symptoms through urinary reflux (inter alia), and can be excluded through flexible cytoscopy and urodynamic tests.^[48][49][50]

Nomenclature

A distinction is sometimes made between "IIIa" (Inflammatory) and "IIIb" (Noninflammatory) forms of CP/CPPS,^[51] depending on whether pus cells (WBCs) can be found in the expressed prostatic secretions (EPS) of the patient. Some researchers have questioned the usefulness of this categorisation, calling for the Meares–Stamey four-glass test to be abandoned.^[52]

In 2007, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) began using the umbrella term Urologic Chronic Pelvic Pain Syndromes (UCPPS), for research purposes, to refer to pain syndromes associated with the bladder (i.e. interstitial cystitis/painful bladder syndrome, IC/PBS) and the prostate gland (i.e. chronic prostatitis/chronic pelvic pain syndrome, CP/CPPS).^[53]

Older terms for this condition are "prostatodynia" (prostate pain) and non-bacterial chronic prostatitis.

Treatment

Chronic pelvic pain syndrome is difficult to treat.^[54]

Psychological and physical therapy

Category III prostatitis may have no initial trigger other than anxiety, often with an element of OCD, panic disorder, or other anxiety-spectrum problem.^[55][56][57] This is theorized to leave the pelvic area in a sensitized condition resulting in a loop of muscle tension and heightened neurological feedback (neural pain wind-up). Current protocols largely focus on stretches to release overtensed muscles in the pelvic or anal area (commonly referred to as trigger points) including digital intrarectal massage, physical therapy to the area, and progressive relaxation therapy to reduce causative stress.

Aerobic exercise can help those sufferers who are not also suffering from Chronic Fatigue Syndrome (CFS) or whose symptoms are not exacerbated by exercise.^[58] Acupuncture has reportedly benefited some patients.^[59]

For chronic nonbacterial prostatitis (Cat III), also known as CP/CPPS, which makes up the majority of men diagnosed with "prostatitis", a treatment called the Wise–Anderson Protocol (aka the "Stanford Protocol"),^[13][14][60] has recently been published. This is a combination of:

• Medication (using tricyclic antidepressants and benzodiazepines)
• Psychological therapy (paradoxical relaxation, an advancement and adaptation, specifically for pelvic pain, of a type of progressive relaxation technique developed by Edmund Jacobson during the early 20th century)
• Physical therapy (trigger point release therapy on pelvic floor and abdominal muscles, and also yoga-type exercises with the aim of relaxing pelvic floor and abdominal muscles).^[13][14]

Biofeedback physical therapy to relearn how to control pelvic floor muscles may be useful.^{[61][62][63][64]} Biofeedback is satisfactory for treatment of chronic prostatitis (with mainly voiding problems) during puberty.^[65]

Pharmacological

A number of medications can be used to treat this disorder. Alpha blockers and/or antibiotics appear to be the most effective with NSAIDs such as ibuprofen providing lesser benefit.^[66]

• Treatment with antibiotics is controversial. Some have found benefits in symptoms^[66] while others have questioned the utility of a trial of antibiotics.^[67] Antibiotics are known to have anti-inflammatory properties and this has been suggested as an explanation for their partial efficacy in treating CPPS.^[18] Antibiotics such as quinolones, tetracyclines and macrolides have direct anti-inflammatory properties in the absence of infection, blocking cytokines such as interleukin-1 (IL-1), interleukin-8 and tumor necrosis factor (TNF), which coincidentally are the same cytokines found to be elevated in the semen and EPS of men with chronic prostatitis.^[68]
• The effectiveness of alpha blockers (tamsulosin, alfuzosin) is questionable in men with CPPS. A 2006 meta analysis found that they are moderately beneficial when the duration of therapy was at least 3 months.^[69]
• An estrogen reabsorption inhibitor such as mepartricin improves voiding, reduces urological pain and improves quality of life in patients with chronic non-bacterial prostatitis.^[70]
• Therapies that have not been properly evaluated in clinical trials although there is supportive anecdotal evidence include: gabapentin, benzodiazepines and amitriptyline.^[71]

Surgery

Transurethral needle ablation of the prostate (TUNA) has been shown to be ineffective in trials.^[72]

Epidemiology

The annual prevalence in the general population of chronic pelvic pain syndrome is 0.5%.^[73] 38% of primary care providers, when presented with a vignette of a man with CPPS, indicate that they have never seen such a patient.^[74] However, the overall prevalence of symptoms suggestive of CP/CPPS is 6.3%.^[75] The role of the prostate was questioned in the etiology of CP/CPPS when both men and women in the general population were tested using the (1) National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI^[76]) —with the female homolog of each male anatomical term use on questionnaires for female participants— (2) the International Prostate Symptom Score (IPSS), and (3) additional questions on pelvic pain. The prevalence of symptoms suggestive of CPPS in this selected population was 5.7% in women and 2.7% in men, placing in doubt the role of the prostate gland.^[77] New evidence suggests that the prevalence of CP/CPPS is much higher in teenage males than once suspected.^[78]

Prognosis

In recent years the prognosis for CP/CPPS has improved with the advent of multimodal treatment, phytotherapy, protocols aimed at quieting the pelvic nerves through myofascial trigger point release and anxiety control, and chronic pain therapy.^[79][80][81]

Notable cases

• John Anderson— Deputy Prime Minister of Australia^[82]
• James Boswell—author of Life of Samuel Johnson^[83]
• John Cleese—British actor^[84]
• Vincent Gallo—movie director^[85]
• Glenn Gould—pianist^[86]
• John F Kennedy— President of the United States of America^[87]
• Howard Stern— radio personality^[88][89]
• William Styron—author (Sophie's Choice)^[90]
• Tim Parks—British novelist, translator and author.

Infection theories

Additional theories and observations include:

• Nanobacteria—In a preliminary 2005 open label study of 16 treatment-recalcitrant CPPS patients, controversial entities known as nanobacteria were proposed as a cause of prostatic calcification and symptoms found in CPPS.^[91] Patients were treated with EDTA (to dissolve the calcifications) and 3 months of tetracycline (a calcium-leaching antibiotic with anti-inflammatory effects,^[92] used here to kill the "pathogens"), and half had significant improvement in symptoms. Scientists have expressed strong doubts about whether nanobacteria are living organisms.^[93][94] Research in 2008 showed that "nanobacteria" are merely tiny lumps of abiotic limestone.^[95][96]
• Viruses—The evidence supporting a viral cause of prostatitis and chronic pelvic pain syndrome is weak. Single case reports have implicated herpes simplex virus (HSV) and cytomegalovirus (CMV) but a study using PCR failed to demonstrate the presence of viral DNA in patients with chronic pelvic pain syndrome undergoing radical prostatectomy for localized prostate cancer.^[97] The reports implicating CMV must be interpreted with caution because in all cases the patients were immunocompromised.^{[98][99][100]} For HSV the evidence is weaker still and there is only one reported case and the causative role of the virus was not proven,^[101] and there are no reports of successful treatments using antiviral drugs such as aciclovir.

See also

• Bladder pain syndrome/interstitial cystitis — a related disease.
• Myofascial Pain Syndrome
• Myofascial Release
• Neuromuscular Therapy
• Trigger Points
• Pelvic myoneuropathy (Theoretical only)

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External links

• Prostatitis at DMOZ
• The Urologic Chronic Pelvic Pain Syndrome Society
• NHS Choices (prostatitis)