Current best practice in the management of cystitis and pelvic pain

Abstract

Bladder pain syndrome (BPS) is a difficult disorder to diagnose and subsequently manage despite having been recognized for more than 200 years according to references in medical literature. There are currently three widely accepted guidelines on BPS: the American Urological Association Guidelines; the Royal College of Obstetricians and Gynaecologists in conjunction with the British Society of Urogynaecologists Guidelines; and the European Association of Urology Guidelines. These guidelines have similarities to each other but also significant differences. This leaves clinicians still confused about this condition and how to appropriately manage the ‘real’ patient. We review the current guidelines and appropriate literature and put forward a clinically usable management strategy.

Introduction

Bladder pain syndrome or interstitial cystitis (BPS/IC) began to appear in the medical literature over 200 years ago. The term interstitial cystitis was first used by Samuel Gross in 1876, ¹ and in 1914 Guy Hunner described specific epithelial damage and ulceration commonly referred to as ‘Hunner’s ulcer’. ² Both of these terms, although still commonly used, are outdated. The overall condition is correctly termed bladder pain syndrome (BPS), part of the chronic pelvic pain spectrum; Hunner’s ulcers are better called Hunner’s lesions. BPS was defined in 2002 by the International Continence Society as ‘the complaint of suprapubic pain related to bladder filling accompanied by other symptoms such as frequency, in the absence of urinary tract infection and other obvious pathology’. ³

Current best practice is set out by three recent evidence-based published guidelines: the American Urology Association (AUA) Guidelines 2014; ⁴ the Royal College of Obstetricians and Gynaecologists (RCOG) in conjunction with the British Society of Urogynaecologists (BSUG) Guidelines 2016; ⁵ and the European Association of Urology (EAU) Guidelines updated in March 2017. ⁶

This review article outlines the key guidance from these sources on the management of BPS and offers a suggestion of a practical approach to managing this challenging condition.

Overview of the guidelines

The AUA guidelines were written following a systematic review of the literature that yielded 117 relevant articles on treatment of BPS. The guidelines are provided in the format of a treatment ladder comprising six levels. The first level states that patient education and understanding of likely outcomes of treatment is paramount in addition to conservative measures. The second-line treatments are physical therapy, pain management and pharmaceutical treatment, both oral and intravesical. Pelvic floor exercises are not recommended. Oral therapeutic options include amitriptyline, cimetidine, pentosan polysulphate and hydroxyzine; intravesical options are, for example, dimethyl sulphoxide (DMSO), heparin and lidocaine. The third-line treatments cover endoscopic interventions such as hydrodistension and, if present, fulguration of Hunner’s lesions possibly followed by injection of triamcinolone (an intermediate acting synthetic glucocorticoid). Fourth-line recommendations are intravesical injection of botulinum A toxin or a trial of neurostimulation. Fifth-line is the use of oral cyclosporine A. Sixth-line is major surgery such as urinary diversion with or without cystectomy, noting that it is essential that patients who reach this stage of management are counselled as to the potential for persistent pain post-surgery. The ladder should be used in a stepwise manner unless the patient’s symptoms and quality of life warrant more aggressive intervention at an early stage and also where a small fibrotic bladder is found early.

The AUA guidelines also specify interventions that are not recommended. These are long-term antibiotics, intravesical Bacille Calmette Guerin (BCG), oral glucocorticoid and high-pressure, long-duration hydrodistension.

The use of these guidelines enables clinicians to adopt a structured approach to treatment of BPS to optimize symptom control and quality of life while minimizing adverse effects. It may also be necessary to use several treatments concurrently. Optimizing management also involves monitoring outcome of treatment – for example, with a validated questionnaire.

The authors state categorically that no single treatment benefits all or most patients with BPS except for fulguration of Hunner’s lesions.

The RCOG/BSUG guidelines were published in December 2016. The initial recommendations match those of the AUA guidelines – that is, applying conservative measures at the outset. However, pain control is also included in the initial management. The next step refers to oral medication and, in particular, amitriptyline and cimetidine. In these guidelines, conservative and oral medication should have failed before consideration is given to intravesical treatment, the strongest evidence of which exists for lidocaine, heparin and intravesical botulinum toxin A. Also, primary care practitioners are encouraged to manage the patients in these initial stages. The subsequent management is then referred to as ‘further treatment options’ and specifies that additional treatment should be offered after pain clinic consultation and multidisciplinary team (MDT) discussion. These options are, fulguration of Hunner’s lesions, posterior tibial or sacral neuromodulation, cyclosporine A, cystoscopic hydrodistension and finally major surgery, as a last resort.

The RCOG/BSUG guidelines differ from the AUA guidelines with regards to hydroxyzine and pentosan polysulphate, which are not recommended as they do not appear to be effective with level B and level A evidence respectively.

The RCOG/BSUG guidelines place strong emphasis on the MDT, recommending referral to a physiotherapist, a pain team, psychological support and counselling and discussion in an MDT meeting. It also recommends adopting a shared care agreement between the pain and urogynaecology teams before returning follow-up to primary care.

The EAU guidelines on chronic pelvic pain are the most recently updated. These guidelines are detailed and emphasize a holistic patient-centred approach. At the outset, as with the other guidelines discussed above, patient education is prioritized. The next recommendation is physical therapy. Evidence is provided to support the use of physiotherapy, specifically transvaginal manual therapy of pelvic floor muscles, specific levator trigger point injections and myofascial physical therapy. However, it is recognized that this depends on the availability of suitably qualified physiotherapists. Female patients in particular may benefit from early referral for relationship and sexual counselling. There is limited evidence for the use of other physical therapies such as electromagnetic, microwave, extracorporeal shockwave therapies and nerve stimulation. Transcutaneous electrical nerve stimulation (TENS), however, has no convincing evidence to support or dispute its use.

Regarding pharmacological agents, the EAU guidelines state that most patients will not obtain symptomatic control with monotherapy and it is likely that multimodal therapy directed at the main symptoms will be necessary. Histamine receptor antagonists are used with variable results. Amitriptyline is the most commonly used tricyclic antidepressant, and where its use is limited by sedative side effects nortriptyline is an alternative. Pentosan polysulphate is associated with subjective improvement in symptoms. The effect improves with treatment duration and can be enhanced by the concomitant use of subcutaneous heparin. Azathioprine has shown efficacy in reducing both pain and lower urinary tract symptoms. Cyclosporin A and methotrexate help pain but do not benefit urgency and frequency. Corticosteroids are not recommended.

Intravesical treatments can be used for medications not active orally and to obtain high intravesical concentration, so minimizing systemic side effects. This is to be balanced against the disadvantages of repeated catheterization and treatments, risk of infection and cost. Agents include local anaesthetic, hyaluronic acid or chondroitin sulphate and heparin. A combination of heparin, lidocaine and sodium bicarbonate was shown to be effective in 94% and showed sustained relief in a high proportion of patients. The evidence for use of hyaluronic acid or chondroitin sulphate is limited, despite relatively mainstream use and benefit.

The guidelines list a number of other agents which have more limited evidence. These include hyperbaric oxygen, cimetidine, prostaglandins, L-arginine, oxybutynin, duloxetine, clorpactin, DMSO and BCG.

Surgical management includes hydrodistension, which is recommended as a diagnostic tool rather than a therapeutic measure due to lack of evidence. However, when used in conjunction with botulinum toxin A, effects were superior to hydrodistension alone. Transurethral resection, fulguration or laser of Hunner’s lesions when present is effective.

Once again, open surgery is considered a last resort in patients refractory to other treatment. Procedures that are employed are urinary diversion without cystectomy, supratrigonal cystectomy with bladder augmentation, subtrigonal cystectomy and cystectomy with ileal conduit formation.

The EAU guidelines provide a less didactic management strategy compared to the AUA guidelines, which perhaps reflects the need to manage each patient on an individual basis.

A practical approach to the management of bladder pain syndrome

The diagnosis of BPS is traditionally one of exclusion.^5,6 The problem here is twofold. First, this may result in patients being over-investigated and a delay to diagnosis. Second, some patients have synchronous conditions presenting with overlapping symptoms which, when detected, may defer a diagnosis of BPS – for example, urinary tract infection (UTI). Clearly other pathology needs to be detected and treated, but the presence of a UTI, for example – a common condition in these patients – does not preclude a simultaneous diagnosis of BPS. That is, patients are allowed to have more than one diagnosis.

Current best practice is set out by the international guidelines summarized above; however, these guidelines still leave the practising clinician trying to decide what to use and when, and relying on limited evidence to support these choices.

The National Institute of Diabetes and Digestive and Kidney Disease produced criteria for diagnosis of IC in 1987 and 1998, but these were intended for application to the research setting and are difficult to use in clinical practice.^7,8 More recently, the European Society for the Study of BPS (ESSIC) has proposed a list of differential diagnoses to be excluded, which is more achievable: malignancy, infection, overactive bladder (OAB), radiation or drug-mediated cystitis, bladder outlet obstruction, urinary tract stones, urethral diverticulum, pelvic organ prolapse, endometriosis, pudendal nerve entrapment, irritable bowel syndrome and diverticular disease. ⁹ The majority of these can be proven or excluded by a careful history, examination, urine dipstick test, renal tract ultrasound and a cystoscopy.

In striving for a positive ‘inclusive’ diagnosis, the most important symptom is pain related to bladder cycling. It is important to listen to the patient; the diagnosis can often be made (or suspected) by listening to the history. However, a very helpful direct question can be: ‘Why do you void so often?’ This can help differentiate between detrusor overactivity – ‘because if I delay I feel I will be incontinent doctor’ – and BPS – ‘if I leave it too long it starts to hurt’. Some patients have difficulty in expressing their symptom as ‘pain’ and so words like ‘uncomfortable’ and ‘pressure’ may be used. A bladder diary can help confirm and quantify urinary frequency and estimate functional volume. Pain score charts such as the O’Leary Sant voiding and pain indices ¹⁰ or the Pelvic Pain and Urgency/Frequency symptom scale (PUF) ¹¹ are not diagnostic but may help future monitoring of treatment by comparison.

Cystoscopy should form part of the diagnostic work up to exclude bladder malignancy. Cystoscopy is not a diagnostic test unless Hunner’s lesions are seen. However, a local anaesthetic challenge test, as described by Nickel and colleagues, may indicate the bladder mucosa as the site of the pain. ¹² Briefly, a flexible cystoscopy on an awake patient is used to look for bladder lesions but also to gently fill the bladder until symptoms occur. Filling is immediately ceased, the bladder is drained and the volume measured. A small volume of alkalinized local anaesthetic is then instilled into the bladder and left for ten minutes. After this period, the bladder is refilled until the same symptoms recur and the second bladder volume is drained off and measured. An increase of greater than 50% of the initial volume suggests bladder mucosal pathology. No significant increase may indicate pelvic pathology external to the bladder or a neuropathic chronic pelvic pain pathology. It should be stressed that this approach is used to guide further investigations and initial treatments and does not provide a definitive diagnosis. It should also be recognized that many clinicians with an interest in BPS would only recommend a cystoscopy under a general anaesthetic. Although this would still be diagnostic, it does not allow the clinician to appreciate the direct effect of bladder filling on the patient with a real-time discussion of their experience with the patient.

Once a diagnosis is reached it is important to accept it and inform the patient of your belief. Honesty is vital in these patients, who have often seen many clinicians previously and have been given an incorrect or unclear diagnosis. It is a difficult diagnosis to reach and it is unfair to criticize previous practitioners, especially if you have had the advantage of time and knowledge of their previous efforts. If you believe the patient has BPS it is important to be able to convey to the patient that the condition is usually not curable but efforts will be made to improve their symptoms and quality of life.

An attempt to improve the patient’s quality of life with simple general measures should be initiated as soon as possible. The RCOG/BSUG guidelines suggest self-management through education, diet and stress management, and non-pharmaceutical strategies such as physiotherapy and psychological help – for example, managing depression, developing coping strategies and cognitive behaviour therapy. It is important that patients are guided correctly as some may have tried self-treating for the wrong condition. For example, drinking vast quantities of cranberry juice in the belief they have bacterial cystitis. In some patients the acidity of this may exacerbate BPS. Others will have turned to traditional pelvic floor (Kegel) exercises. These may also be deleterious as they increase pelvic tone and some BPS patients would benefit more from being taught by an experienced physiotherapist to relax their pelvic wall muscles with Thiele’s exercises. ¹³

Hunner’s lesions should be treated with surgery if present. Endoscopic resection or fulguration of these lesions often relieves pain, sometimes completely. Sadly, the lesions and the pain usually recur and the patient must be made aware of this. A small study of endoscopic ablation of Hunner’s lesions by Payne and colleagues reported a 76% improvement in symptoms. ¹⁴

Recommendations for the pharmacological management of BPS are similar across the guidelines.^4–6

Pharmacological approaches for BPS can be divided into general and bladder-specific. General medications include simple analgesia, amitriptyline, hydroxyzine and cimetidine. These latter act via neuromodulation and histamine pathways. Traditionally, they are combined as triple therapy. One study that reviewed the available evidence found only two randomized controlled trials for amitriptyline, and that the use of antidepressant medication is not supported sufficiently by the current literature. ¹⁵ It may, however, be effective and well tolerated. In a systematic review by Dimitrakov and colleagues, efficacy for hydroxyzine was not proven; however, due to study limitations the evidence is currently inconclusive. ¹⁶ In again limited studies, cimetidine was shown to be effective, although on histopathological analysis the pharmacological mechanism has not been proven. ¹⁷

More specific treatments are based on the theory that BPS is caused by a failure of the glycosaminoglycan (GAG) layer of the bladder. Hyaluronic acid, heparin sulphate, heparin, chondroitin 4-sulphate and 6-sulphate, dermatan sulphate and keratan sulphate are the main components of the GAG layer of the bladder. These are diverse proteoglycans that allow permeability but prevent adherence of infective agents. The GAG layer is a continuous covering of the urothelium that is proposed to be disrupted in some way in BPS, supporting the use of exogenous components as treatment. Pentosan polysulphate sodium is a synthetic compound only available on a named patient basis in the UK. It is not recommended in the RCOG/BSUG guidelines, although it is included in the AUA and EAU guidelines. Nickel and colleagues report that high-dose (900 mg daily) pentosan polysulphate was more likely than placebo to provide an improvement in Clinical Global Improvement assessment and quality of life. ¹⁸

Bladder instillations are usually directed at restoration of the GAG layer, although local anaesthetic or steroids have been used as non-specific anti-inflammatory and analgesic agents. For example, a study by Cox and colleagues supported the use of a submucosal injection of triamcinolone for Hunner’s lesions, with 70% of patients very much improved. ¹⁹ Heparin, pentosan polysulphate, DMSO, hyaluronic acid and chondroitin sulphate have been used as monotherapy or in combination. A study of 48 patients treated three times weekly for 3 months with intravesical heparin showed that 56% had a clinical remission within the 3 months. ²⁰ DMSO given twice weekly for 2 weeks showed a 53% improvement versus 18% in a placebo group in a study of 33 patients. ¹⁶ Chondroitin monotherapy improved global response assessment in a meta-analysis of 213 patients, ²¹ and in a smaller study in conjunction with hyaluronic acid there was symptomatic improvement with a sustained response up to 36 months. ²²

The authors’ approach to management is to treat suspected mucosal pathology (as directed by a local anaesthetic challenge test) with bladder-specific medications. Oral treatment with pentosan polysulphate is initially tried for at least 3 months as its effects may take some time to manifest. Patients are fully counselled that this is an off-licence treatment in the UK. In the event of treatment failure, intravesical GAG layer replacement instillations are then used. Third-line therapy to be discussed with individual patients includes alkalinized lignocaine instillations or botulinum toxin A therapy.

Treatments may improve some symptoms but not others. For example, there may be improvement in pain but less so in urinary frequency. Multiple individualized treatments should be offered – for example, anticholinergics, botulinum toxin A or neurostimulation – in addition to the ongoing GAG layer treatments.

In cases where the local anaesthetic challenge test has suggested the pain may not be emanating from the mucosa, pelvic pathology external to the bladder is assessed by pelvic imaging or laparoscopy. In the absence of this, more general therapeutic approaches are taken, usually with an increasing dose of amitriptyline with or without the addition of hydroxyzine or cimetidine.

Management of BPS must be individualized and empiric. The results of the local anaesthetic challenge test should not be rigidly adhered to if treatment fails; alternative treatments should be tried and the clinician should be amenable to this. Combination therapy has been less frequently studied.

Where all other therapies have failed to provide adequate symptom control and quality of life, open surgery should be considered.^4–6 Surgical options include urinary diversion without cystectomy, supratrigonal cystectomy with bladder augmentation, subtrigonal cystectomy and cystectomy with ileal conduit formation. In a study of 45 patients who underwent ileocystoplasty and supratrigonal cystectomy with refractory BPS and Hunner’s lesions, pain and frequency, urgency and nocturia were significantly improved and bladder capacity increased. ²³ A study of 23 patients with refractory IC that directly compared subtrigonal cystectomy with supratrigonal cystectomy reported that these techniques offer a similar improvement in symptoms but that supratrigonal cystectomy offered better functional results. ²⁴

Conclusions

BPS is a distressing condition that is difficult to diagnose and treat. Up-to-date, evidence-based guidelines provide an excellent background to diagnosis and management but can be difficult to follow in real-world practice. Diagnosis is based on basic medical principles of careful history taking. Investigations tend to be supportive and aimed at excluding other pathologies rather than being diagnostic. Management should be individualized and symptom-based, but tends to follow a progressive therapeutic ladder. This may be supported by a local anaesthetic challenge test. Clinicians should be amenable to multimodal therapies and polypharmacy and empirical treatment strategies. BPS is a chronic and usually incurable condition. Sufferers should be supported to come to terms with this and management should be aimed at improving quality of life.