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Chronic Pelvic Pain Syndrome: A Clinical Enigma a

a

Avi Stein MD , Tal May MD & Yoram Dekel MD

a

a

Department of Urology, Carmel Medical Centre, Haifa, Israel Published online: 28 May 2015.

Click for updates To cite this article: Avi Stein MD, Tal May MD & Yoram Dekel MD (2014) Chronic Pelvic Pain Syndrome: A Clinical Enigma, Postgraduate Medicine, 126:4, 115-122 To link to this article: http://dx.doi.org/10.3810/pgm.2014.07.2789

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C L I N I C A L F E AT U R E S

Chronic Pelvic Pain Syndrome: A Clinical Enigma

DOI: 10.3810/pgm.2014.07.2789

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Avi Stein, MD 1 Tal May, MD 1 Yoram Dekel, MD 1 Department of Urology, Carmel Medical Centre, Haifa, Israel 1

Abstract: Chronic nonbacterial prostatitis is an ill-defined, painful clinical condition that is characterized by various nonspecific symptoms, some of which are related to urination or the male reproductive organs. Urologists diagnose this particular condition when the symptoms are not associated with urinary bacterial growth before and after transrectal prostate massage. In this review, we describe the recommended and optional tests that can be performed in these cases. There is significant overlap between chronic nonbacterial prostatitis and other unexplained pain conditions, raising the question as to whether the prostate is the culprit. The sources and mediators of pain and the psychological aspects of this complex condition are discussed. Treatments consist of traditional antibiotics and α-blockers. Because the pain relief is often temporary, patients seek other solutions. Various therapeutics have been introduced to satisfy the expectations of patients and physicians. We discuss other pain medications, as well as intraprostatic drug injections and shockwave therapy. Importantly, however, not all of these suggestions have been widely accepted by urologists or pain clinics. Keywords: chronic prostatitis; CPPS; nonbacterial prostatitis; chronic pain

Introduction

Chronic bacterial (class II) prostatitis can result from partially treated acute prostatitis (class I) or can gradually develop after repeated urinary tract infections. Acute prostatitis is beyond the scope of this review (see Appendix). Class IIIa and IIIb, chronic nonbacterial prostatitis, differ only in the presence or absence of white blood cells in the patient’s urine specimen. These 2 conditions have a common clinical presentation and are termed chronic prostatitis/chronic pelvic pain syndrome (CP/ CPPS). This review expounds on the theories about the etiology of this disease and the necessary tests for excluding other clinical conditions. Patient management is also discussed from a medical perspective and based on other aspects of this challenging syndrome.

Materials and Methods Correspondence: Avi Stein, MD, Department of Urology, Carmel Medical Centre, 7 Michal Street, Haifa 34362, Israel. Tel: 972-4-825-0843 Fax: 972-4-825-0122 E-mail: [email protected]

This article is based on a selective review of the literature up to 2013 on the etiology, assessment, and management of CP/CPPS. The expanded search terms prostatitis, chronic nonbacterial prostatitis, chronic abacterial prostatitis, chronic pelvic pain syndrome, and prostatodynia were combined with truncated keywords that described the type of publication, such as random, double-blind, random allocation, placebo, clinical trial, and comparative study. We limited the search to full text articles and studies in English. We used the Pubmed and Cochrane Library search engines.

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Chronic Prostatitis: Differential Diagnosis

Chronic prostatitis is diagnosed after a thorough investigation of the patient’s history. Further diagnostic steps include urine analysis and urine culture before and after prostate massage.1,2 Once bacterial growth is detected by culturing, chronic bacterial prostatitis can be diagnosed. If there is no bacterial growth in the culture and symptoms persist, the patient is likely to be diagnosed with chronic nonbacterial prostatitis (CP/ CPPS), which covers approximately 90% of all patients presenting with the particular symptoms. The symptoms vary from slight significant discomfort and may imitate those associated with other diseases and other organ systems, such as the gastrointestinal system. The pain and discomfort may be located in and migrate between the perineum, anus, low back, penis, testis, scrotum, and inguinal area. Fatigue, dysuria, frequent urination, and voiding difficulties are also common.

Chronic Bacterial Prostatitis (Class II)

Chronic prostatitis may follow an acute case of prostatitis. Approximately 5% of acute prostatitis cases progress to chronic disease if not adequately treated. A meticulous medical history reveals $ 1 event of urinary tract infection in approximately 15% to 20% of patients with chronic bacterial prostatitis. This disease is diagnosed by isolating the bacteria in the post–prostate massage urine sample. Various pathogens may be involved, including the most common bacterial culprits in urinary tract infections, pathogens that cause urethritis (chlamydia and ureaplasma) and viruses, which are more difficult to cultivate in the urine. Treatment regimens consist of antibiotics that are based on the bacterial sensitivity observed in the culture. The treatment must continue for 6 to 12 weeks, with the goal of completely eradicating the pathogen. If the bacteria are sensitive to multiple agents, it is best to choose an antibiotic with good penetration into the prostate. The pathophysiologic theory for this disease posits that bacteria colonize deep in the prostatic ducts, restricting their access to blood and thus rendering ineffective short-term antibiotic treatments that are typically effective against a simple urinary tract infection. Other treatments are discussed below.

Chronic Nonbacterial Prostatitis (Class IIIa and IIIb) or Chronic Pelvic Pain Syndrome

Chronic prostatitis/chronic pelvic pain syndrome is the most prevalent of these prostate inflammatory conditions, 116

constituting approximately 90% of all cases. In addition to the symptoms mentioned above, this disease is frequently accompanied by low back pain, diarrhea, tenesmus, and other gastrointestinal symptoms with no other clear cause. A recent publication discussed the relationships and overlap between urologic and nonurologic unexplained clinical conditions. Chronic fatigue syndrome, fibromyalgia, inflammatory and irritable bowel disease, interstitial cystitis, and painful bladder syndrome have all been described to overlap with CPPS. The bowel symptoms have the most robust evidence of overlap.2

Pathogenesis

Various theories have been suggested to explain CP/CPPS,3 and several animal models have been employed to understand the etiology of this disease. Certain models suggest that an autoimmune response is the trigger for this syndrome.4–6 Elevated levels of prostaglandin E2 (4- to 6-fold above normal), an inflammatory marker, and low endorphin levels have been observed in the serum of patients with CP/CPPS. After treatment, prostaglandin E2 levels have been observed to decrease, whereas endorphin levels increase. Oxidative stress is another possible pathogenic pathway. Shahed and Shoskes6 performed molecular assays of oxidative stress markers by evaluating gene expression. They collected 300 expressed prostatic secretions from 100 men with CPPS and found that oxidative stress markers were elevated in patients with chronic prostatitis class IIIa and IIIb. These markers decreased significantly after antibacterial and antioxidant treatment.

Neurologic Factors

It is important to recall that the prostate gland has abundant autonomic innervation from both the sympathetic and parasympathetic nervous systems.7 Growing evidence supports a significant neuropathic component to CPPS. Pain is generally of 2 types: nociceptive or inflammatory. Nociceptive pain results from the activation of nociceptive primary afferent neurons, including C and Aδ fibers, mainly by chemical or thermal signals that indicate damage or danger. Inflammatory pain results from the interaction between inflammatory mediators and the nervous system, causing sensitization phenomena, which typically lead to spontaneous pain in the absence of a stimulus. The sensitization can manifest at 2 levels—at the peripheral nerve terminal (peripheral sensitization) or at the dorsal horn of the spinal cord (central sensitization). In both mechanisms, sensitization is a state of hyperexcitability in which normal

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CPPS Diagnosis, Etiology, and Treatment

sensory input is sustained. Both manifestations contribute to symptoms other than the previously mentioned spontaneous pain, such as hyperalgesia and allodynia. Hyperalgesia is the increased severity of pain in response to a painful stimulus. Allodynia is a painful response to a stimulus that is not normally painful. In peripheral sensitization, inflammation triggers a cascade that activates nociceptive neurons, including C and Aδ fibers, and sensitizes them by reducing the activation threshold, resulting in nociceptive pain. This condition expands the pain field and creates a condition of persistent and recurrent pain in the absence of a stimulus.8 Central sensitization is thought to play an important role in chronic pain. Central sensitization occurs at the level of the secondary neuron in the dorsal horn of the spinal cord and is caused by abnormal neuronal regeneration within the pain pathway as a result of chronic signals or signals from damaged peripheral nerves.9 Another important category of pain is neuropathic pain. Neuropathic pain is pain of neural origin. In CP/CPPS, pain may be considered of neural origin when it is triggered by peripheral nerve injury; alternatively, certain cases of neural damage are thought to be caused by an excitotoxic state (dysfunctional pain).

Psychological Factors

Psychological factors have been considered to be an important part of the etiology and symptomatology of CPPS. These factors include many personality variables, such as clinical depression, panic disorders, anxiety, poor social interaction, and poor coping skills that manifest as a magnification of any situation.10 Furthermore, all these psychological factors make the pain worse. Pain may increase and contribute to psychological stress. Together, these factors create a vicious cycle. The most common finding is psychological stress.11 In a large case/control study, depression and panic disorders appeared to play an important role. Depression and panic disorders were more common in men with chronic pelvic pain than in controls.12 As early as 1954, Green and Dean raised the possibility that patients with chronic prostatitis suffer from psychoneuroses.13 Mellan et al14 strengthened this assertion and described it as prostate neuroses. Almost 30 years later, Janssen et al15 confirmed that neurotic disorders are present in almost all CP/CPPS patients. Patients with sexual problems, asthenic patients, passive and dependent patients, and patients with homosexual tendencies are more prevalent in the population with this syndrome.

The professionals treating these individuals cannot ignore the fact that many of them have a stressful personality. However, it is true that suffering from such a challenging disease may be the cause rather than the result of the personality changes.

Quality of Life

The quality of life of these patients has been widely studied. These patients have a clear tendency to catastrophize their symptoms.16–18 A recent study using the Self-Administered Leeds Assessment of Neuropathic Symptoms and Signs questionnaire determined that a large proportion of patients with chronic pelvic pain present with neuropathic features and report a decreased quality of life compared with the general population. Patients with neuropathic pain scored 4.28 and 5.45 points lower on the physical (P = 0.053) and mental (P = 0.008) component summaries, respectively.19

Clinical and Laboratory Tests to Exclude a Urologic Cause of This Syndrome

A detailed history is mandatory, and it should include the duration and location of the pain or discomfort. Lower urinary tract symptoms must be recorded, and a voiding diary should be obtained. Any details regarding urethral discharge events are to be documented and further investigated via appropriate laboratory tests. Previous cultures and the dosage and duration of antimicrobial treatments should be documented in detail. The most effective and scientific approach to qualifying and quantifying the clinical situation involves the use of questionnaires. The most commonly used questionnaire is the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI; Figure 1), which has been translated into and validated in many languages. Symptoms may be dominant in various organs. A recent publication reported the determination, prevalence, and impact of the locations and types of pain in over 1500 CPPS patients. Perineal pain/discomfort was the most common symptom (63%), followed by testicular pain (58%), pain in the pubic area (42%), and pain in the penis (32%); pain during ejaculation and voiding was reported in 45% and 43% of the patients, respectively.20 Inguinal, lower back, and thigh pain as well as pain in the psoas muscle region have also been described as bothersome.21 Irritable bowel symptoms and allergies are frequent comorbidities.13,19,22 Chronic pelvic pain syndrome primarily presents in individuals with differing clinical phenotypes based on various etiologies that tend to have distinct combinations of symptoms and progression trajectories. A system was required to bridge the gap between current symptom-based

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Figure 1.  National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI).

Reprinted from The Journal of Urology, 170(3), Hetrick DC, Ciol MA, Rothman I, Turner JA, Frest M, Berger RE, Musculoskeletal dysfunction in men with chronic pelvic pain syndrome type III: a case-control study, 828–831, Copyright 2003, with permission from Elsevier.

diagnosis and future mechanistic approaches to diagnosis. Nickel et al10 termed this the “snow-flake hypothesis” and suggested a phenotypic evaluation of symptoms by introducing the UPOINT questionnaire (urinary, psychosocial, organ specific, infection, neurologic/systemic, and tenderness of skeletal muscles; Table 1), which evaluates the symptoms of CP/CPPS according to the various organ systems potentially involved in the pathophysiology of CPPS.23,24

rectal examination. Polymerase chain reaction analysis of urine samples is required to exclude sexually transmitted diseases if urethral discharge is present. Additional suggested examinations include: uroflow, a voiding diary, residual urine volume, and urinary cytology. Other examinations include semen culture, urodynamic study, cystoscopy, serum prostate-specific antigen, and ultrasound or computed tomography imaging of the urinary tract.

Diagnostic Evaluation

Treatment

Necessary examinations include a urinalysis and urine culture performed before and after prostate massage via the digital 118

The treatment of this complex syndrome is neither simple nor uniform, and is typically frustrating to the physician

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CPPS Diagnosis, Etiology, and Treatment

Table 1.  The UPOINT Questionnaire Domain

Clinical Description

Urinary

Chronic Prostatitis Symptom Index urinary score . 4 Patient complaint of bothersome urgency, frequency, or nocturia Flow rate , 15 mL/s or obstructed pattern Postvoid residual urine volume . 100 mL Clinical depression Poor coping or maladaptive behavior, eg, evidence of catastrophizing (magnification or rumination in regard to symptoms, hopelessness) or poor social interaction Specific prostate tenderness Leukocytosis in prostatic fluid Hematospermia Extensive prostatic calcification Exclude patients with clinical evidence of acute (acute infection) or chronic bacterial prostatitis (recurrent infection that is localized to prostate specimen between infections) Gram-negative bacilli or Enterococcus localized to prostatic fluid Documented successful response to antimicrobial therapy Pain beyond abdomen and pelvis Irritable bowel syndrome Fibromyalgia Chronic fatigue syndrome Palpable tenderness or painful muscle spasm or trigger points in perineum or pelvic floor or sidewalls during digital rectal examination

Psychosocial

Organ specific

Infection

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Neurologic/systemic conditions

Tenderness of skeletal muscles

Levofloxacin for chronic prostatitis/chronic pelvic pain syndrome in men: a randomized placebo-controlled multicenter trial, Nickel JC, Downey J, Clark J, et al, Urology 62(4) Copyright © John Wiley and Sons. Reproduced by permission of John Wiley and Sons.

and the patient. It requires much patience, sympathy, and understanding on the part of the physician regarding the physical and mental difficulties experienced by the patient.

Antibiotics There is little debate regarding the treatment of chronic bacterial prostatitis (class II), in which a pathogen is isolated from the infection site. As CPPS is a nonbacterial clinical entity, the effect of antibiotics is debatable. Quinolones and macrolides have been most commonly used. Diagnostic and culture techniques need to be refined, and the pathogenic role of atypical bacteria should be defined. The somewhat beneficial effect of antibiotics could also be explained as a placebo effect. Nickel et al25 reported that symptom improvement was not significantly different from that with placebo in a randomized controlled trial. The duration of antibiotic treatment should not exceed 4 to 6 weeks. If antibiotic treatment is ineffective, it should be stopped and replaced with another therapeutic modality.

α-Blockers Many CPPS treatment protocols and regimens include α-blockers as monotherapy.9−12 α-Blockers have traditionally been postulated to inhibit smooth muscle tonus and therefore

increase urine flow; more recently, α-blockers have been suggested to inhibit prostate cell proliferation and induce prostate apoptosis.26,27 In 2008, a multicenter, randomized, double-blind, placebo-controlled trial was conducted to evaluate the efficacy of alfuzosin, an α-adrenergic receptor blocker, in reducing symptoms in men with CPPS. Surprisingly, the study did not support the use of alfuzosin for reducing the symptoms of CP/ CPPS in men who have not received prior treatment with an α-blocker. The combination of antibiotics, anti-inflammatory drugs, and α-blockers has been reported to be more effective than monotherapy.28,29

Anti-Inflammatory Drugs Steroidal and nonsteroidal anti-inflammatory drugs may provide brief, temporary relief.30 A randomized controlled trial of rofecoxib showed a significant improvement in quality of life compared with placebo.31 Pentosan polysulfate is a semisynthetic mucopolysaccharide that is similar to the naturally occurring glycosaminoglycans that form a protective barrier in the urinary epithelium. It is registered as a treatment for interstitial cystitis, and has shown some success in treating CPPS.32 Finasteride is an inhibitor of the enzyme 5-α reductase. It prevents the transformation of testosterone to dihydrotestosterone, therefore reducing the prostate volume and arresting

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prostate growth. Finasteride has been studied in CPPS but was not effective as a monotherapy.33

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Pain Management

All pain relievers offer some relief for patients with CPPS. Pregabalin (Lyrica) has been used in different clinical settings involving neuropathic chronic pain to block the electrical signals of neurotransmitters. A recent study included 218 men assigned to receive pregabalin, and reported that 47% of the patients had $ a 6-point decrease in the NIHCPSI total symptom score at 6 weeks compared with 35.8% of the patients in the placebo group.34 Recently, Nickel et al35 investigated the concept of targeted therapy against nerve growth factor, which is known to be involved in the development and manifestation of CPPS. They studied tanezumab, a humanized monoclonal antibody that specifically inhibits the interaction of nerve growth factor with its receptors on nociceptive neurons. Tanezumab was reported to reduce chronic pain in patients with interstitial cystitis/bladder pain syndrome. However, the study did not confirm this effect in CPPS patients, and larger population studies may be necessary.

Other Treatments for Patients Not Responding to Medications (Low Recommendation Level) Acupuncture

Chen and Nickel36 followed a protocol involving 3 sets of acupuncture points (30 points total, 8 electrically stimulated points) alternatively stimulated twice weekly for 6 weeks. The patients completed pre- and posttreatment NIH-CPSI questionnaires. Twelve men underwent a minimum of 6 weeks of acupuncture treatment. After an average follow-up of 33 weeks, significant decreases were observed in the total NIH-CPSI (28.2 to 8.5), NIH-CPSI pain (14.1 to 4.8), NIH-CPSI urinary (5.2 to 1.3), and NIH-CPSI quality of life (8.8 to 2.3) scores.

Myofascial Trigger Point Assessment and Release Therapy in Conjunction With Paradoxical Relaxation Therapy A group at Stanford evaluated myofascial trigger point assessment and release therapy in combination with paradoxical relaxation therapy in 138 patients. The case study analysis revealed a significant improvement.37

Transcutaneous Electrical Nerve Stimulation Chabal et al38 assessed a variety of treatment outcomes in long-term users of transcutaneous electrical nerve stimulation 120

who had a 40- to 60-month history of chronic pelvic pain, and observed a significant reduction in the utilization of pain medication and physical therapy. Control groups were absent in many of the referenced studies, and therefore there is not a strong level of confidence in the results.

Prostate Heat Therapy The delivery of high temperatures to the prostate via a transrectal balloon has been attempted for many years but has been abandoned because of the low efficiency. Transurethral microwave thermotherapy (TUMT) falls in the 300- to 3000-MHz range of the electromagnetic spectrum. This microwave-generated heat energy causes irreversible damage to prostate cells without markedly affecting the urethra. The interaction of the instrument with tissue ultimately results in the generation of heat via the electromagnetic field oscillation of free charges and the polarization of small molecules. The resulting molecular kinetic energy increases the temperature in the tissue. Transurethral microwave thermotherapy is delivered through an antenna located in a specially designed catheter, and the location of the heating center can be changed according to the size of the prostate. The temperature is elevated gradually over a few minutes up to 50°C and is maintained for approximately 60 minutes. These devices are used to treat benign prostatic hyperplasia. The side effects are mostly irritation and obstruction, eventually requiring a few days of bladder drainage after the procedure. Choi et al39 reported on the TUMT treatment of 61 patients with treatment-resistant CPPS and 17 with prostatodynia. Among the CPPS patients, 46% experienced a normalization of their symptoms, and 31% had an improved leukocyte count in expressed prostatic secretions. Nickel and Sorenson40 observed a short-term response to TUMT in a smaller group of CPPS patients. One of our team authors (Stein) treated 12 patients and observed limited complete responses and some temporary symptom relief.41 Higher temperatures have been tested in combination with a cooling system (cooled TUMT).42

Intraprostatic Injections The penetration of antibiotics into prostate tissue is limited by the blood–prostate barrier.43 This limitation has led to the development of a more direct method of delivering drugs into the prostate: the injection of medications directly into prostatic tissue. Antibiotics are often combined with lidocaine and steroids. Transurethral, transperineal, and transrectal approaches have been attempted to reach the prostate.

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CPPS Diagnosis, Etiology, and Treatment

Injections have been used in various protocols and schedules and have an overall temporary success rate of , 50%.44 Botulinum A injections around the prostate have been reported for the treatment of bladder outlet obstruction due to prostatic hypertrophy. Patients with CPPS have also reported some pain relief after botulinum injections. The published studies had a relatively short follow-up period.45–47 Shock waves to the perineal area have been introduced by Zimmerman et al.48 A group of 60 comparable patients was treated with a reflector that produces shock waves directed at different points of the perineum. A comparable control group received sham treatment. The treatment protocol involved 3000 weekly shock waves (maximum total energy flow density: 0.25 mJ/mm2; frequency: 3 Hz) for 4 weeks. The results indicated that there was relief in certain pain categories as measured by the NIH-CPSI. Our group has had the limited experience of treating 15 patients according to the same protocol with a similar instrument produced by Medispec. The short-term results were somewhat less impressive, but some relief was obtained (publication pending the long-term results).

Conclusion

Chronic prostatitis/chronic pelvic pain syndrome is a common condition among men of a wide age range, and it has a detrimental effect on quality of life. The etiology, pathogenesis, and optimal treatment of CP/CPPS remain unknown. The pain is not specific and may mimic numerous other clinical situations. Because of the apparent complexity and diversity of the etiologic and pathogenetic factors in CP/CPPS, 1 drug is unlikely to be effective in all patients. Various pharmacologic and nonpharmacologic therapies have been studied in clinical trials, but most have had limited efficacy in alleviating symptoms. Additional randomized controlled studies that include biomarkers and genetic markers related to objective measures are necessary to progress in the understanding and treatment of this disease.

Conflict of Interest Statement

Avi Stein, MD, Tal May, MD, and Yoram Dekel, MD, have no conflicts of interest to declare.

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CPPS Diagnosis, Etiology, and Treatment

Appendix Classification

The World Health Organization suggests the following classification: I. Acute bacterial prostatitis II. Chronic bacterial prostatitis III. CPPS a. Inflammatory (with white blood cells in the urine after prostatic massage) b. Noninflammatory (with no white blood cells in the urine after prostatic massage)

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Acute Bacterial Prostatitis

Acute bacterial prostatitis is characterized as a severe and acute disease with dysuria, a significant fever, and voiding

difficulties. It often simulates an event of urosepsis, and differential diagnosis may be difficult. Rectal examination is recommended only after adequate serum levels of antibiotics are achieved to avoid the potential spread of bacteria into the blood stream. The patient should be managed as a septic patient with intravenous fluid resuscitation, blood and urine cultures, and an oxygen mask. If urine drainage is required, a temporary cystostomy tube should be used. Urethral catheters may cause local irritation of the urethra and further block the para-urethral glands. If the fever does not resolve and leukocytosis persists, prostate abscess should be suspected. A transrectal ultrasound or computed tomography is then recommended, and if an abscess is verified, transurethral, transrectal, or transperineal drainage can be performed.49

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Chronic pelvic pain syndrome: a clinical enigma.

Chronic nonbacterial prostatitis is an ill-defined, painful clinical condition that is characterized by various nonspecific symptoms, some of which ar...
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