Interstitial cystitis

Transcription

1 Interstitial cystitis Ilse Truter, PharmITCom Consulting Bladder Normal protective bladder lining Thinning of the protective bladder lining Pinpoint bleeding (glomerulations) on the bladder wall Hunner s ulcer in the bladder wall (Source: This article will provide a general overview of interstitial cystitis (IC), also known as painful bladder syndrome (PBS), a disorder that is characterised by inflammation of the bladder. Introduction Cystitis is inflammation of the bladder. 1 Interstitial cystitis (IC), also known as painful bladder syndrome (PBS), was first described in IC is a form of chronic, debilitating noninfectious bladder inflammation that causes suprapubic, pelvic and/or abdominal pain, urinary frequency and urgency with incontinence. 1,3,4 As a result of the use of multiple diagnostic criteria, there is variation in its prevalence and delays in its diagnosis. IC affects predominantly middle-aged women, and significantly decreases quality of life. 3 People with IC/PBS often suffer needlessly for an average of five to seven years before an accurate diagnosis is made. 3 The impact of IC/PBS on a person s quality of life is illustrated in Figure 1. Even though people with IC/PBS can appear healthy, many have to curtail work and leisure activities and have difficulty sleeping and maintaining sexual intimacy. 3 With treatment, most patients improve, but cure is rare. However, there are therapies that can help to relieve the debilitating symptoms. 3 Pain, urinary urgency and urinary frequency Limitations on sexual intimacy Curtailed activities Sleep deprivation Reduced ability to work Reduced quality of life Figure 1: Impact of IC/PBS on quality of life 3 S Afr Pharm J 11

2 Definition IC/PBS is difficult to define, but is generally described as a chronic disease of unknown aetiology characterised by vague bladder pain and non-specific urinary symptoms, such as urgency and frequency. 2 The course of the disease is usually characterised by flares and remissions. 5 Symptoms vary in severity and frequency, and generally include: 3 Pelvic pain, pressure or discomfort. A persistent urge to void, or urinary frequency, are typically associated with these sensations. Absence of infection or other pathology. Pelvic pain, sometimes described as pressure or discomfort, is the defining symptom. 3 As the bladder fills, pain increases and as the bladder empties, pain often diminishes. 3 The pain, in turn, can increase the feeling of urgency, which is usually relieved by voiding. In 1988, the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) suggested the use of diagnostic criteria. While these criteria are useful for research, they are too restrictive to be used in diagnosing IC/PBS. 5 Also, up to 60% of patients who have been clinically diagnosed with IC/PBS by experienced clinicians were overlooked when using the NIDDK definition and criteria. 2 In 2002, the International Continence Society (ICS) proposed the term painful bladder syndrome (PBS). Later, the European Society for the Study of PBS/IC (ESSIC) decided to rename PBS as bladder pain syndrome (BPS), yet in the literature the term interstitial cystitis/painful bladder syndrome (IC/PBS) or painful bladder syndrome/interstitial cystitis (PBS/IC) are commonly used. Epidemiology The prevalence of IC/PBS varies because of the different definitions and methods that are used to evaluate it. In older studies, IC/PBS seems to be relatively rare (18.1: women and 10.6: men) compared to more recent studies which estimate the prevalence to be / in women and 40-70/ in men. 2 Although the exact incidence of IC is unknown, the disorder appears to be more common than once thought and may underlie other clinical syndromes, for example, chronic pelvic pain. White people are more susceptible and up to 90% of cases occur in women. 1 The female to male ratio ranges from 5:1 to 10:1. 2 However, IC/BPS may be underdiagnosed in men because some men are misclassified as having chronic prostatitis. 3 The onset of IC/PBS usually occurs between years of age. 5 The median age at diagnosis is years, with men generally being diagnosed at a younger age. 2 Children are occasionally diagnosed with IC/PBS. 5 According to the literature, the only definite risk factor for IC/PBS is the female gender. 3 Other possible risk factors include heredity and previous urinary tract infection. 3 The non-ulcer type of IC/PBS occurs in approximately 90% of patients. The more severe form of the disease (in about 10% of patients) involves Hunner s ulcers, which are lesions that affect all of the layers of the bladder wall and appear as brownish-red patches on the bladder mucosa. 5 Aetiology The exact cause of IC/PBS is unknown, but bladder damage may trigger the condition. 3 It may be autoimmune, allergic or infectious, although no convincing evidence confirming a viral, bacterial or fungal cause has been found. 5 IC/PBS may involve loss of protective urothelial mucin (abnormalities of the bladder surface mucin), with penetration of urinary potassium and other substances into the bladder wall, activation of sensory nerves and smooth muscle damage. 1 Mast cells may mediate the process, but their exact role is unclear. Therefore, IC involves urothelial permeability changes, with mast cell activation and neurogenic inflammation (see Figure 2). Damage of the protective bladder lining Numerous possible stimuli (drugs, hormones) Upregulation of purinergic pathway of urothelial cells Increased permeability to urine solutes Sensory nerve endings activation Mast cell activation and degranulation Peripheral and central neural upregulation Chronic inflammatory bladder disorder Figure 2: Proposed underlying pathophysiology of IC/PBS 2 S Afr Pharm J 12

3 Diagnosis IC is often underdiagnosed or improperly diagnosed. 5 There are no definite diagnostic tests for IC/PBS. The condition is difficult to diagnose since biological markers have not yet been confirmed, and it mimics other conditions. 3 Therefore, diagnosis is by history and exclusion of other disorders. The general approach to diagnosing IC/PBS is empirical. IC is initially asymptomatic, but symptoms appear and worsen over the years as the bladder wall is damaged. Suprapubic and pelvic pressure or pain occurs, usually with urinary frequency (up to 60 times per day) or urgency. 1,3 These symptoms worsen as the bladder fills and diminish when patients void. Other conditions must be excluded, for example urinary tract infection, an overactive bladder, bladder carcinoma and the medication effects of cyclophosphamide, aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) and allopurinol. A midstream urine sample usually shows no bacteriuria. In some patients, symptoms worsen during ovulation, the week before menstruation, with seasonal allergies, physical or emotional stress, or sexual intercourse. 2,5 People with sensitive skin, irritable bowel syndrome (IBS), vulval pain syndrome (vulvodynia), pelvic floor muscle spasm and endometriosis (in endometriosis, symptoms are worse during menses) are also being studied, as IC/PBS seems to occur more often in these people. 3 Foods with a high potassium content, for example, citrus fruits, chocolate, caffeinated drinks and tomatoes, may cause exacerbations. If the bladder wall becomes scarred, bladder compliance and capacity decrease, causing urinary urgency and frequency. Fibrosis of the bladder wall is possible. Incontinence is not typical of IC/PBS, but if present, other diagnoses must be sought. 5 Dyspareunia (on deep penetration) is not uncommon in patients with IC/PBS 5 and sexual dysfunction is therefore often found in female patients with IC/PBS. Six tools have been suggested for a basic diagnostic assessment of IC/PBS: 3 History (voiding symptoms, pelvic pain or discomfort, urinary frequency and urgency, and nocturia). Physical examination (pelvic examination in women and digital rectal examination in men). Urinalysis (may be entirely normal or may show microscopic haematuria or pyuria). Urine culture. Cytology (when indicated, to rule out carcinoma of the bladder). Diagnosis is therefore suggested by symptoms after testing has excluded more common disorders that cause similar symptoms (for example, urinary tract infections, pelvic inflammatory disease, chronic prostatitis or prostatodynia, or diverticulitis). Other tests that may be performed are cystoscopy with hydrodistension under anaesthesia (to pinpoint haemorrhages or fissures with bleeding, called glomerulations), potassium sensitivity test (to identify worsening symptoms caused by a potassium solution irritating the bladder wall), and an anaesthetic challenge (to identify improvement in symptoms after intravesical instillation of an anaesthetic). 3 Cytoscopy is performed when it is essential to rule out other pathology, and particularly underlying malignancy. Cytoscopy with hydrodistension can assist in diagnosing Hunner s ulcers (benign bladder ulcers) and glomerulations more easily. A biopsy is usually required to exclude bladder carcinoma, dysplasia or tuberculosis. 5 Figure 3 shows the evaluation of patients with suspected IC/ PBS. 5 Assessment of symptoms with a standardised symptom scale, or during intravesical KCl infusion (potassium sensitivity testing), may improve diagnostic accuracy, but this is not routine practice. Treatment Primary care providers vary in their treatment approaches to IC/PBS. Many focus on diet, self-help strategies and oral therapy before trying other therapies. 3 According to the literature, more than 180 different treatments have been tried in IC, but in the absence of definite diagnostic tests and standardised clinical criteria, data regarding the efficacy of therapies are limited. 2 Up to 90% of patients improve with treatment, but cure is rare. Treatment varies, but generally includes dietary changes, bladder training, bladder stretching, pharmacological therapy with pentosan, analgesics and antispasmodics, and intravesical therapies. No single treatment has proven effective, but a combination of at least two or more non-surgical treatments is recommended before surgery is considered. Any treatment that can improve a patient s discomfort with minimal morbidity is certainly of value. 6 Treatment can be divided into nonpharmacological treatment, pharmacological treatment, intravesical pharmacotherapies and various other therapies. Non-pharmacological treatment Supportive therapies include general measures that can alleviate symptoms or prevent exacerbations. Psychosocial support is important because it is an essential part of any chronic pain treatment plan. Support groups of persons with the same disorder may prove to be useful. Depression is not uncommon in IC, as well as other common co-morbid diseases, such as inflammatory bowel disease. All factors associated with symptom exacerbation should be avoided. Therefore, treatment usually includes avoidance of tobacco, alcohol, foods with a high potassium content and spicy foods. Other substances that may trigger symptoms include coffee and tea, caffeinated drinks, citrus fruits and drinks, artificial sweeteners, tomatoes, and food additives and preservatives. 3 Stress reduction and biofeedback may also help. Bladder training can also be used, as well as a timed voiding protocol. Patients should be asked to keep a 24-hour log of voiding activity for frequency of urination and voiding patterns, because patients may be accustomed to an abnormal voiding pattern. 5 S Afr Pharm J 13

4 Patient with possible interstitial cystitis History Physical examination Bladder neck tenderness on bimanual examination 24-hour voiding log Commonly associated conditions Migraine, vulvodynia, fibromyaigia, chronic fatigue syndrome, irritable bowel syndrome Triggers Diet, sexual activity, allergens Symptoms Urgency, frequency, suprapubic/ pelvic pain, dyspareunia, flareups and remissions Rule out Preinvasive and invasive lesions with urine cytology or cystoscopy and biopsy Urinary tract infections with urine culture and sensitivity Confirmation Cystoscopy and hydrodistension under anaesthesia or office cystoscopy and trial of therapy; consider potassium sensitivity test Interstitial cystitis Figure 3: Evaluation of patients with suspected IC/PBS 5 Pharmacological treatment The most commonly used drug is pentosan (pentosan polysulfate sodium or PPS), a heparin similar to urothelial glycosaminoglycan. It has been found to be modestly beneficial. 2 It is the only oral medication approved by the United States Food and Drug Administration( FDA) for the treatment of IC/PBS. 2,3 It is well tolerated and has a favourable side-effect profile. 5 Doses of 100 mg orally three times a day may help to restore the bladder s protective surface lining. Improvement may not be noticed for two to four months. 1 Therefore, administration for a prolonged period may be required before a clinical response is noted, since oral treatment leads to a low concentration in the bladder (only 6% of PPS is excreted in urine). 2 Increased doses of PPS (300 mg and 600 mg daily) have not been associated with greater efficacy, but with more frequent adverse effects. 2 PPS treatment, within six months after diagnosis, is associated with greater efficacy compared with late treatment. 2 The most commonly reported side-effects of pentosan include nausea, diarrhoea, headache and alopecia. Antihistamines are also considered an important oral treatment. Hydroxyzine taken once before bedtime may help by directly inhibiting mast cells or by blocking allergic triggers. Although evidence is limited, hydroxyzine is considered by many urologists as a first-line treatment. 2 Its anxiolytic and anticholinergic effects, along with its ability to inhibit bladder inflammation, may explain the efficacy of hydroxyzine. The dose starts at 25 mg taken daily at bedtime, and should be slowly titrated to mg. 2 Prolonged administration (three to four months) may be needed before any beneficial effect is shown. 2 Tricyclic antidepressants block pain arousal and are widely used in pain clinics for their pain blocking effects. 5 Amitriptyline is commonly used. 2,3 Its mechanism of action entails regulation of pain through modulation of neuronal dysfunction. The median dose is 75 mg daily (range of mg per day). 2 Because of the anticholinergic side-effects, patients should start on the lowest possible dose (10 mg daily) and titrate up to the effective dose. Imipramine (25-50 mg orally once daily) is also used. NSAIDs in standard doses may also relieve pain. 1 Some patients claim they get relief from aspirin or a NSAID, probably because mast cell degranulation releases prostaglandins and leukotrienes. 5 S Afr Pharm J 14

5 Because IC/PBS may be an autoimmune disease in some patients, different immunosuppressant medicines have been tested. 6 For example, cyclosporine, a calcineurin inhibitor, may act in IC/PBS through inhibiting the activation of T cells or mast cells. 2 However, data regarding its effectiveness are limited. Oral cimetidine was found to be very effective, with significant symptom improvement occurring in the only randomised controlled trial (RCT) available. 2 L-Arginine is a substrate for nitric oxide (NO) synthase, and has been used in IC/PBS based on data that NO synthase activity is decreased in the urine of IC/PBS patients. However, two RCTs reported limited efficacy. 2 Routine urine cultures in IC/PBS are negative. Yet, some patients have reported that antibiotics might decrease their symptoms, but an RCT failed to show benefit from orally administered antibiotics. 2 Antibiotics are therefore not standard therapy for IC/PBS, although IC/PBS may signify a subclinical infection in some cases, so some patients may benefit from long-term antibiotic therapy. 6 Numerous other oral treatments have been used in IC/PBS, such as steroids, montelukast and methotrexate, but data are scarce and mostly based on small or poorly designed studies. RCTs for the treatment of IC/PBS are urgently needed. Sedatives, for improved sleep, may reduce the IC/PBS symptoms. The combination of two oral medications for an enhanced treatment response is sometimes recommended. Intravesical pharmacotherapies Intravesical therapy involves instilling a single agent or cocktail of agents into the bladder. Therefore, it provides intense local drug concentrations in the bladder, avoids systemic side-effects and eliminates the problem of low levels of urinary excretion with orally administered agents. 5 It is generally used as a second-line treatment, or in conjunction with oral therapy or other types of conservative treatment. 3 Intravesical treatments for IC/PBS were analysed in a Cochrane review published in ,7 Nine studies addressed intravesical treatment for IC/PBS, but the evidence was inconclusive in all of the instillations. 7 Only Bacilllus Calmette- Guérin (BCG) and oxybutynin, a medicine commonly taken orally to stop unwanted bladder contractions, seemed to be well tolerated and gave the most promising results, although the evidence is extremely limited. 2,7 Oxybutynin instillation was associated with increased bladder capacity, reduced frequency, improved quality of life scores and fewer dropouts. 7 Alkalinisation of urine ph did not make any clear difference. 7 Dimethyl sulfoxide (DMSO) is the only intravesical medication approved by the FDA for IC/PBS. Although DMSO is an antiinflammatory agent, it seems to have some analgesic and muscle relaxant properties as well. 5 DMSO instilled into the bladder through a catheter and retained for 15 minutes, may deplete substance P and trigger mast cell granulation (50 ml every one to two weeks for six to eight weeks, repeated as needed, relieves symptoms in up to half of patients). 1 However, the side-effects of DMSO (a garlic-like smell and taste) make it almost impossible to perform a real placebocontrolled RCT. In the Cochrane review, resiniferatoxin was not associated with sustained differences in the reported review outcomes, but pain during instillation and withdrawal from treatment was significantly more common. 7 Intravesical instillation of 15 ml of a solution containing 100 mg of pentosan or units of heparin, plus 80 mg of lidocaine and 3 ml of sodium bicarbonate, may benefit patients unresponsive to oral medication. Intravesical instillation of hyaluronic acid is under study. 1 Other therapies Bladder hydrodistension, cytoscopic resection of Hunner s ulcers, and sacral nerve root (S3) stimulation or transcutaneous electrical nerve stimulation, may help some patients. 1,2 Bladder distension is one of the oldest treatments for IC/PBS. 6 Bladder hydrodistension is carried out while the patient is under anaesthesia. The urologist then performs a cytoscopic examination and distends the bladder with saline solution or sterile water beyond its normal capacity for a few minutes. Many patients with IC/PBS have spasms of the pelvic floor muscles that contribute to symptoms of pelvic pain, urgency and frequency. Physical therapy, with biofeedback for pelvic floor relaxation, may be helpful in such patients. 5 From a complementary and alternative medicine perspective, nutraceuticals that have been studied for the treatment of IC/PBS include calcium glycerophosphate, L-arginine, mucopolysaccharides, bioflavonoids and Chinese herbs. 6 Acupuncture has also been used. 8 Surgery (for example, partial cystectomy), bladder augmentation (enlarging the bladder by attaching an isolated segment of bowel to it), neobladder (a urinary reservoir made from a bowel or stomach segment often used to replace the bladder after cystectomy and urinary diversion) is rarely done. Surgery is a last resort for patients with intolerable pain that is refractory to all other treatments. Its outcome is also unpredictable, because in some patients, symptoms will persist. Summary of treatment options In summary, treatments for IC/PBS include dietary/lifestyle interventions, oral medication, intravesical instillations and, in some cases, surgery. Various other therapies have also been tested. However, success rates are generally modest, and there is little consensus as to the best form of treatment for this condition. 7 Figure 4 illustrates a possible treatment algorithm for IC/ PBS, based on best available evidence with a focus on the less toxic or controversial therapies. 2 The cost/benefit ratio should always be considered before any of the more invasive treatments, or those with significant adverse effects, are recommended. These treatments should be reserved for refractory cases. S Afr Pharm J 15

6 Oral therapies Pentosan, hydroxyzine, amitriptyline Supportive therapies (psychosocial, behavioural, physical) ± analgesia Consider No response Intravesical therapies BCG, oxybutynin, DMSO, pentosan, sodium hyaluronate, hydrodistension Consider No response Other therapies Immunosuppression, electric neuromodulation Consider Reconstructive surgery Figure 4: Treatment algorithm for IC/PBS 2 Conclusion No response IC/PBS is believed to be a syndrome, rather than a disease. It has numerous aetiologies and it is difficult to accurately define and diagnose the condition. Various studies have reported an increased incidence of the condition. IC is often mistaken for other gynaecological or urological disorders, and patients are often only diagnosed with IC/PBS in an advanced stage. Therefore, health care practitioners should bear an IC diagnosis in mind in patients presenting with chronic urinary symptoms, after excluding other more common or obvious causes. If there are symptoms that do not respond to oral therapies, if the diagnosis is in doubt, or if the practitioner is uncomfortable in treating the disorder, a referral to a specialist should rather be made. Currently, no single treatment exists that can relieve all symptoms in all patients with IC/PBS. This is probably due to poor understanding of the pathophysiology of IC/PBS and more research is needed to understand the condition. From a pharmacist s point of view, only supportive care can be given. The pharmacist should acknowledge the challenges of living with IC/PBS, reassure patients that the condition can be diagnosed despite the absence of specific markers, explore treatment options, and support diet and self-help strategies. 3 References 1. The Merck Manual.18 th edition. Whitehouse Station: Merck Research Laboratories; Moutzouris DA, Falagas ME. Interstitial cystitis: an unsolved enigma. Clin J Am Soc Nephrol. 2009;4: What you need to know: understanding interstitial cystitis/painful bladder syndrome. Association of Reproductive Health Professionals (ARHP) [homepage on the Internet]. c2010. Available from: uploaddocs/understandingicpbsfactsheet.pdf 4. Gardella B, Porru D, Ferdeghini F, et al. Insight into urogynecologic features of women with interstitial cystitis/painful bladder syndrome. Eur Urol. 2008;54: Metts, JF. Interstitial cystitis: urgency and frequency syndrome. Am Fam Physician. 2001;64 (7): [homepage on the Internet]. c2010. Available from: Erickson DR. Interstitial cystitis: update on etiologies and therapeutic options. J Womens Health Gend Based Med. 1999;8 (6): Dawson TE, Jamison J. Intravesical treatments for painful bladder syndrome/ interstitial cystitis. [Cochrane Review]. In: The Cochrane Library, Issue 4, Oxford: Update Software. 8. Whitmore KE. Complementary and alternative therapies as treatment approaches for interstitial cystitis. Rev Urol. 2002;4(suppl 1):S28-S35. S Afr Pharm J 16