EAU guidelines on chronic pelvic pain

European Urology European Urology 46 (2004) 681–689 EAU Guidelines on Chronic Pelvic Pain M. Falla,*, A.P. Baranowskib, C.J. Fowlerb, V. Lepinardc, J.G. Malone-Leed, E.J. Messelinke, F. Oberpenningf, J.L. Osborneg, S. Schumacherh a Institute of Surgical Sciences, Department of Urology, Sahlgrenska University Hospital, 413 45 Göteborg, Sweden University College London Hospital, London, UK c Clinique Saint-Louis, Angers Cedex, France d Royal Free and University College Medical School, London, UK e Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands f Rheinische Friedrich-Wilhelms-University, Bonn, Germany g University College Hospitals, Great Portland, UK h Zayed Military Hospital, Abu Dhabi, United Arab Emirates b Accepted 29 July 2004 Available online 19 August 2004 Abstract Objectives: On behalf of the European Association of Urology (EAU) guidelines for diagnosis, therapy and followup of chronic pelvic pain patients were established. Method: Guidelines were compiled by a working group and based on current literature following a systematic review using MEDLINE. References were weighted by the panel of experts. Results: The full text of the guidelines is available through the EAU Central Office and the EAU website (www.uroweb.org). This article is a short version of this text and summarises the main conclusions from the guidelines on management of chronic pelvic pain. Conclusion: A guidelines text is presented including chapters on prostate pain and bladder pain syndromes, urethral pain, scrotal pain, pelvic pain in gynaecological practice, role of the pelvic floor and pudendal nerve, general treatment of chronic pelvic pain and neuromodulation. These guidelines have been drawn up to provide support in the management of the large and difficult group of patients suffering from chronic pelvic pain. # 2004 Elsevier B.V. All rights reserved. Keywords: Guidelines; Chronic pelvic pain; Prostate pain syndromes; Bladder pain syndrome; Prostatitis; Interstitial cystitis; Evaluation; Diagnosis; Treatment; Follow-up 1. Introduction ‘‘Chronic pelvic pain’’ is a non-malignant pain perceived in structures related to the pelvis. It can be difficult to manage because it is often impossible to identify the pathophysiological origin. Nociceptive pain must prove persistent or recurrent over six months before being described as chronic. If non-acute pain mechanisms are identified then the pain is considered chronic, irrespective of the time course. There is no * Corresponding author. Tel. +46 31 342 10 00; Fax: +46 31 41 49 72. E-mail address: [email protected] (M. Fall). ideal classification for the conditions included in the set that constitutes chronic pain syndrome. The terms used in these guidelines follow the most recent recommendations for the terminology by the International Continence Society (ICS) [1], which are based on the Axial Structure of the International Association for the Study of Pain (IASP) classification (Table 1). 2. Prostate pain syndrome Prostatitis is a poorly defined condition that encompasses the three elements, lower urinary tract 0302-2838/$ – see front matter # 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2004.07.030 682 M. Fall et al. / European Urology 46 (2004) 681–689 Table 1 Classification of chronic pelvic pain syndromes symptoms (LUTS), evidence of inflammation and involvement of the prostate. These features may exhibit varying degrees of involvement since the term primarily portrays a symptom set. The NIDDK system is the preferred classification identifying four major subtypes of disease [2] (Table 2). An EAU working group has suggested a practical classification that divides chronic prostatitis into chronic bacterial, in which a pathogen Table 2 Classification of prostatitis according to NIDDK/NIH I. II. III. IV. Acute bacterial prostatitis (ABP) Chronic bacterial prostatitis (CBP) Chronic pelvic pain syndrome (CPPS) A. Inflammatory CPPS: WBC in semen/EPS/voided bladder urine-3 (VB3) B. Noninflammatory CPPS: no WBC semen/EPS/VB3 Asymptomatic inflammatory prostatitis (histological prostatitis) M. Fall et al. / European Urology 46 (2004) 681–689 has been demonstrated, and culture-negative disease, where inflammation is found microscopically in the absence of an identified pathogen [3]. In 5 to 10% of cases, prostatitis is shown to have a bacterial aetiology. In the remaining proportion the symptoms have been attributed to ‘‘Chronic non-bacterial prostatitis’’, ‘‘Prostadyndia’’ or ‘‘Chronic prostatitis associated with chronic pain syndrome’’. The latter is defined as discomfort or pain in the pelvic region with negative culture of specimens and insignificant numbers of white blood cells in prostate-specific specimens including semen, expressed prostatic secretions and urine collected after prostatic massage. There is neither overt renal tract disease nor evidence of urethritis, other inflammation, urogenital cancer, urethral stricture or neurological disease. The aetiology and pathogenesis of this larger group of patients is extremely speculative and therefore the new term ‘‘Prostate pain syndromes’’ seems more appropriate. The diagnosis rests on a clinical history, symptoms evaluation, examination and analysis of urine and prostate-specific specimens. Commonly, a course of antibiotics is used as a therapeutic test rather than a diagnostic response. 2.1. Medical treatment Current treatment is directed at symptom management to improve life quality and the involvement of pain management services. Benefit may be wrought by alpha blockers [4–6], muscle relaxants [7,8] and antibiotics [9–14]. Patients who effect a response to antibiotics should be maintained on such for at least six weeks. Should a relapse occur, continuous low-dose antimicrobial treatment should be used [7]. Although analgesics are given to most patients, efficacy data are sparse [7]. Other options have been advocated but need justification through evidence. These include non-steroidal anti-inflammatories (NSAID), immunotherapy [15], 5-alphareductase inhibitors [16,17] and anticholinergics [7]. 2.2. Interventional treatments Various physical therapies have been claimed to improve symptoms although rigorous efficacy data are lacking. Heat therapy as microwave energy applied trans-urethral or trans-rectal has been reported to induce favourable effects in some patients [18,19]. Surgical treatment is limited to circumstances where another indication exists [20,21]. 683 3. Bladder pain syndrome (Interstitial cystitis) The collective term ‘‘Interstitial cystitis’’ includes a variety of conditions most commonly identified by symptoms. The classical ulcer disease (Hunner’s ulcer) is found in as few as 10% up to 50% of cases [22,23]. The diagnostic criteria described by the NIDDK [24] were formulated for research purpose and reach a diagnosis through exclusion, inappropriate in clinical care (Table 3). Since symptoms invariably define the clinical condition the term ‘‘Painful bladder syndrome’’ or ‘‘Bladder pain syndrome’’ is more apposite. The prevalence of bladder pain syndrome is between 5 and 16 per 100,000 of the population [25–27] although higher prevalence up to 0.5% have been reported. The aetiology is not known. No bacterial or viral cause for bladder pain syndrome has been found despite the use of sophisticated detection methods. Many hypotheses have been proposed, the more popular including mast cell activation [23], defects in the urothelial glycosaminoglycan (GAG) coating [28,29] autoimmune disease [30,31], toxic agents [32] and neuroendocrine-immune interactions [33, 34]. None of these hypotheses have been tested properly and have invalid status. Table 3 Research definition of interstitial cystitis described by NIDDK Workshop on IC, 28–29 August 1987 [24] Automatic inclusions  Hunner’s ulcer Positive factors  Pain on bladder filling relieved by emptying  Pain (suprapubic, pelvic, urethral, vaginal or perineal)  Glomerulations on endoscopy  Decreased compliance on cystometrogram Automatic exclusions  <18 years old  Benign or malignant bladder tumours  Radiation cystitis  Tuberculous cystitis  Bacterial cystitis  Vaginitis  Cyclophosphamide cystitis  Symptomatic urethral diverticulum  Uterine, cervical, vaginal or urethral cancer  Active herpes  Bladder or lower ureteral calculi  Waking frequency < five times in 12 hours  Nocturia < two times  Symptoms relieved by antibiotics, urinary antiseptics, urinary analgesics (for example phenazopyridine hydrochloride)  Duration <12 months  Involuntary bladder contractions (urodynamics)  Capacity >400 cc, absence of sensory urgency 684 M. Fall et al. / European Urology 46 (2004) 681–689 Bladder pain syndrome is diagnosed on the basis of symptoms, examination, urine analysis and cystoscopy with hydro-distension and biopsy. All patients describe pain, urinary frequency and nocturia. The pain, which is sometimes extreme, typically increases with bladder filling and is located suprapubically. This may radiate to the groins, vagina, clitoris, penis, rectum or sacrum and it is relieved by voiding although it soon returns [24]. Classical ulcer disease and bladder pain syndrome demonstrate different clinical presentations and age distributions [35]. They can be discriminated noninvasively and respond differently to treatment. Classical ulcer disease is a destructive inflammation which in some patients leads to contracted, fibrotic bladders and upper tract outflow obstruction. This progression does not occur in non-ulcer bladder pain syndrome. The two conditions differ in their histopathology, immunology and neurobiology [23]. Classical ulcer disease displays reddened mucosal areas often associated with small vessels radiating towards a central scar, sometimes covered by a small clot or fibrin deposit [35]. The scar ruptures with increasing bladder distension with a characteristic ‘‘waterfall’’ type of bleeding. There is a strong association between classical ulcer disease and reduced bladder capacity under anaesthesia [23,35]. Non-ulcer disease displays a normal bladder mucosa at initial cystoscopy. The development of glomerulations after hydro-distension is a diagnostic sign still lacking evidential authority. Biopsies help to support the clinical diagnosis of classical ulcer disease and to exclude carcinoma in situ and tuberculous cystitis [36]. Several tests, for example the measurement of potassium chloride permeability have been proposed but evidence is meagre. The Table 4 Level of evidence and grade of recommendation Level Type of evidence 1a 1b 2a 2b 3 4 Meta-analysis of randomized trials At least on randomized trial One well-designed controlled study without randomization One other type of well-designed quasi-experimental study Non-experimental study (comparative study, correlation study, case reports) Expert committee, expert opinion Grade Basis for recommendation A Clinical studies of good quality and consistency including at least one randomized trial Well-conducted clinical studies without randomized trials Absence of directly applicable clinical studies of good quality B C O’Leary Sant symptom index [37] aids diagnosis and helps to measure outcome. 3.1. Medical treatment The treatment of bladder pain syndrome has yet to be defined from evidence. Tables 4–6 summarise the current literature on this subject. 4. Urethral pain syndrome Urethral pain syndrome is diagnosed in patients presenting with dysuria, with or without frequency, nocturia, urgency and urge incontinence in the absence of evidence of urinary infection. It is germane that the methods typically used to identify urinary infection are extremely insensitive and some patients may have genuine infection that has not been recognised. Modern automated laboratory methods will not detect colony counts below 104 colony Table 5 Medical treatment of IC Analgesics Corticosteroids Hydroxyzine Cimetidine Amitriptyline Sodium PPS Antibiotics Prostaglandins L-arginine Immunosuppressants Oxybutynin Tolterodine Gabapentin Suplatast tosilate Quercetin Level of evidence Grade of recommendation Comment 4 3 2b 1b 1b 1a 1b 3 1b 3 3 3 3 3 3 C C B A B A A C C C C C C C C Indications limited to cases awaiting further treatment Corticosteroids not recommended as long-term treatment Standard treatment Preliminary data so far Standard treatment Standard treatment Limited role in the treatment of IC Insufficient data on IC, adverse effects Effect in IC uncertain Insufficient data on IC, adverse effects Limited indication in IC Limited indication in IC Preliminary data so far Preliminary data so far Preliminary data so far 685 M. Fall et al. / European Urology 46 (2004) 681–689 Table 6 Intravesical, interventional, alternative and surgical treatment of Interstitial cystitis Intravesical anesthetics Intravesical pentosanpolysulfate (PPS) Intravesical heparin Intravesical hyauronic acid Intravesical dimethyl sulfoxide (DMSO) Intravesical Bacillus Calmette-Guérin (BCG) Intravesical clorpactin Intravesical vanilloids Bladder distension Electromotive drug administration (EMDA) Transurethral resection (TUR), coagulation and LASER Nerve blockades/epidural pain pumps Sacral neuromodulation Bladder training Manual and physical therapy Diet Acupuncture Hypnosis Psychological therapy Surgical treatment Type of evidence Nature of recommendation 3 1b 3 3 1b 1b 3 1b 3 3 n.a. C A C C A Not recommended beyond clinical trials Not recommended Not recommended beyond clinical trials C B A/B 3 3 3 3 3 3 C B B B C C No data B A 3 n.a. Comment Data contradictory Obsolete Insufficient data on IC Hunner’s ulcers only For crisis intervention, effect on pain only Not recommended beyond clinical trials Patients without pain Data contradictory Ultima ratio, experienced surgeons n.a. = not applicable forming units per ml (cfm/ml) of urine, when in the presence of symptoms an appropriate diagnostic threshold should be 102 cfm/ml. Nearly one third of acutely dysuric women with urinary infection caused by Escherichia coli, Staphylococcus saprophyticus or Proteus spp. have mid-stream urine colony counts in the range 102 to 104 cfm/ml [38–40]. Urethral trauma arising from intercourse may cause pain and dysuria. Women with pelvic floor dysfunction describe the symptoms as do postmenopausal women. 5. Scrotal pain syndrome Acute scrotal pain includes torsion of the testis and appendices and requires immediate diagnostic and therapeutic attention. In contrast, chronic scrotal pain is a symptom that has lasted at least six months. It can be unilateral or bilateral, continuous or intermittent. In order to clarify the diagnosis, each component of the scrotum should be palpated and, if possible the site of the pain should be localised. A digital rectal examination is mandatory and the integrity of the pelvis and spine should be checked. It is essential to perform ultrasonography of the scrotal contents to seek for lesions within the testicular parenchyma and epididymis. Ultrasound should also include examination of the prostate, upper urinary tract and bladder. The urine should be analysed. MRI and CT scans are optional [41]. The differential diagnoses to consider include chronic epididymitis, painful cystic lesions, sequelae following trauma or orchitis or pain referred from prostatitis, prostate cancer, anorectal disorders or distal ureteric stones. 5.1. Medical treatment The first-line treatments in chronic epididymitis are antibiotics and nonsteroidal anti-inflammatory drugs. Patients with extragenital disease are treated according to the cause. Patients without identifiable lesions have to be treated conservatively, using antibiotics and methods for managing chronic pain. It is not unusual to be unable to find an explanation for chronic scrotal pain. If microcalcifications are identified in the testes during the assessments, the patients should be followed up, not because the calcifications have anything to do with the symptoms but because there is a slight chance of the development of testicular cancer [42]. 5.2. Surgical treatment A surgical procedure will cure an average of 50% of patients with an identifiable intrascrotal lesion [43–46], with superior results from painful hydrocoel, spermatocoel and varicocoel. Surgery is also the method of choice in chronic epididymitis associated with recurrent urinary infection and urethral stricture, in this specific case to ablate the stricture. Postvasectomy pain, like chronic epididymitis or sperm granuloma 686 M. Fall et al. / European Urology 46 (2004) 681–689 may also be accessible to surgical management. Posthernia repair orchalgia with presumed nerve entrapment will require surgical exploration when all other means have failed. In patients with chronic orchalgia where no cause has been found surgery may be contemplated but the results are not good [43]. Favourable results have been reported from microsurgical testicular denervation [47]. 6. Pelvic pain in gynaecological practice Pelvic pain presenting to the gynaecologist will feature a remedial cause in approximately 70% of cases, leaving 30% unexplained [48]. Clues to the aetiology are provided by the history, including the nature, frequency and site of the pain, precipitating factors, effect of the menstrual cycle, a record of sexually transmitted diseases, vaginal discharge and sexual trauma. Abdominal and pelvic examination will exclude gross pathology as well as demonstrating the site of any tenderness. Vaginal and endocervical swabs may identify pathogens. Cervical cytology screening is advised. Pelvic ultrasound should always be used, MRI where indicated. Laparoscopy is the most useful invasive investigation [49,50]. Primary dysmenorrhoea begins with the onset of ovulatory menstrual cycles and tends to decrease following childbirth. Secondary dysmenorrhoea suggests a pathological process such as endometriosis and pelvic infection. Endometriosis is suggested by a history of secondary dysmenorrhoea and often dyspareunia, with reduced uterine mobility, and sometimes adnexal masses. The bladder, ureter and bowel may be involved. Endometriosis may be halted, but not cured, by hormone treatment. The best surgical results are achieved laparoscopically in specialist centres. Despite extensive surgery, pain may persist. Chronic pelvic pain may arise from gynaecological malignancy or childbirth-related injuries. It is essential to consider pain associated with urinary and gastrointestinal disease. 7. Pelvic floor and pudendal nerve The pelvic floor has three functions; support, contraction and relaxation. Underactive pelvic floor muscles result in urinary and faecal incontinence and pelvic organ prolapse. Overactive muscles may result in high outflow resistance producing low urinary flow rates, obstructed defaecation and dyspareunia [51,52]. Pelvic floor overactivity is thought to be a major factor contributing to chronic pelvic pain. The cycle usually starts with increased muscle tension which may arise from several causes. Pelvic floor muscle overactivity results in several symptoms including pain which in turn causes anxiety and distress that aggravate and perpetuate the muscle contraction. Pudendal nerve entrapment leading to chronic compression of the pudendal nerve arise pelvic floor anomalies. It can result in a perineal pain located either anteriorly in the vagina and vulval region, or posteriorly in the anorectal region. It is suggested by a one-sided, burning sensation, exacerbated by unilateral rectal palpation which may be associated with delayed pudendal motor latency on the painful side. Pain associated with denervation and renervation may be caused by many lesions of the pelvic organs other than dysfunction of the pelvic floor muscles. Magnetic resonance imaging (MRI) is the investigation of choice to show both neural tissue and surrounding structures. The examination should include scrutiny of the anatomy along the course of the pudendal nerve. Improvement in pelvic floor muscle function can be achieved by pelvic floor education, including such techniques as pelvic floor relaxation and biofeedback. 7.1. Psychological factors in chronic pelvic pain Psychiatric disorders may be involved in some cases of chronic pelvic pain including somatisation and somatoform disorders. These are characterised by physical symptoms that cannot be accounted for by a general medical condition, the effect of a substance or mental disorder. They cause clinically significant distress and impairment [53]. Somatisation is an avoidance coping strategy. Childhood physical and sexual abuse are strongly associated with later somatisation [54], including chronic pelvic pain. When no reasons for chronic pelvic pain have been identified it is important to ask about physical and sexual abuse when taking the history because of the consequences for the therapy chosen. On the other hand, chronic pelvic pain must not be used to stigmatise patients as being abused when no such history is forthcoming. Depression is a state of significantly decreased emotional, psychological and social functioning with neurovegetative symptoms lasting at least two weeks. A subclinical depression is often overlooked in both men and women and can worsen or prolong chronic pelvic pain [55]. M. Fall et al. / European Urology 46 (2004) 681–689 8. General treatment of chronic pelvic pain 8.1. Analgesia Clinical trial evidence is signally lacking in this field. Whilst paracetamol should be considered for mild pain, research is needed to define its role in chronic pelvic pain [56]. There are very few data on the use of NSAIDs and even less on COX2 selective drugs with studies focused on dysmenorrhoea. However, this subject is inchoate and lack of data should not necessarily be seen as indicative of futility. Non-selective, low potency NSAIDs should be used first and are most likely to be helpful when the pain has an inflammatory component. More potent NSAIDs should be used only when low-potency drugs have failed to be helpful. COX2 selective drugs are an alternative to non-selective drugs in patients with an increased risk of gastric complications such as those over 65 years of age, receiving prolonged, high-dose therapy, taking other medications that may induce gastrointestinal bleeding or with a previous history of gastrointestinal problems. NSAIDs should be taken with food and, if appropriate, gastric protective agents. The benefits of the NSAIDs must outweigh the risks. All NSAIDs are contraindicated in active gastrointestinal ulceration/bleeding and renal disease and may seriously exacerbate asthma and produce fluid retention. If stronger analgesics are needed, NSAIDs may be continued because of their synergistic action with opioids in controlling pain [57,58]. Opioids have a role in chronic non-malignant pain [59] but their use in urogenital pain is not well studied. All other reasonable treatments must have been tried and failed. The addictive nature of opioid medication means that various safeguards must be followed and the decision to instigate long-term opioid therapy should be made by an appropriately trained specialist in consultation with another physician, preferably the patient’s primary care doctor. Morphine is the first-line drug unless there are contraindications or special indications for another drug. The drug should be prescribed in a slow-release form. The neuropathic analgesics; tricyclic antidepressants or anticonvulsants may be more helpful in patients with nerve injury or central sensitisation. Serotonin reuptake inhibitors are less effective than tricyclic antidepressants. In some countries gabapentin is licensed for use in chronic neuropathic pain and is said to produce a more natural sleep state at night than the antidepressants [60]. Many practitioners no longer use carbamazepine because of its potentially serious side effects. 687 The N-methyl-D-aspartate (NMDA) receptor complex is an important channel for development and maintenance of chronic pain. The NMDA antagonist, ketamine may be helpful in nerve injury or central sensitisation [61], opioid-resistant pain [62] and intractable pelvic cancer pain. Ketamine is highly addictive and great care is required if a patient is to be managed at home on parenteral ketamine. A change in the number, distribution and type of sodium channels can result in altered mechanosensitivity, thermosensitivity and chemosensitivity [63]. Thus low plasma doses of the sodium channel blocker, lidocaine have been used to reduce neuropathic pain and sensory phenomena without any effect on nociception [64,65]. Infusions must be performed by trained practitioners. A single infusion may have benefit for several months. The oral analogue, mexiletine may be helpful in similar circumstances. 8.2. Nerve blocks These specialist procedures may be performed for diagnostic reasons and therapeutic benefit. Nerve blocks should be performed as part of a pain management package and not in isolation. Neurolytic blocks are rarely indicated for benign processes and to proceed with one may induce terrible consequences. 8.3. Transcutaneous electrical nerve stimulation (TENS) Surface electrical nerve stimulation relieves pain by stimulating myelinated afferents and thereby activating segmental inhibitory circuits. Urinary frequency may also be reduced. Continuous stimulation seems preferable for treating pain. The maximum tolerable intensity just below the pain threshold should be used. The frequencies used vary widely from 1 to 100 Hz. Clinical experience suggests starting with the higher frequencies as the best option. The standard recommendation has been 0.5 to 2 hours treatment twice daily. In bladder pain syndrome suprapubic, vaginalanal and tibial nerve sites have been tested using TENS, all with some success. The outcome is better in classical ulcer disease [66,67]. 8.4. Sacral neuromodulation Sacral root is based on the observation that electrical stimulation of sacral nerves modulates neural reflexes in the pelvis. It may benefit patients with refractory motor urge incontinence, urinary retention, chronic pelvic pain, neuropathic pain and complex regional pain syndromes as well as bladder pain syndrome and refractory pelvic floor dysfunction and pelvic pain [68–70]. 688 M. Fall et al. / European Urology 46 (2004) 681–689 References [1] Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Am J Obstet Gynecol 2002;187:116–26. [2] Krieger JN, Nyberg Jr L, Nickel JC. 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