European Journal of Obstetrics & Gynecology and Reproductive Biology 175 (2014) 30–37
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Review
Interstitial cystitis/painful bladder syndrome: epidemiology, pathophysiology and evidence-based treatment options N.F. Davis a,b,*, C.M. Brady b, T. Creagh a a b
Department of Urogynaecology, Beaumont Hospital, Dublin, Ireland Department of Urology, Cork University Hospital, Cork, Ireland
A R T I C L E I N F O
A B S T R A C T
Article history: Received 18 August 2013 Received in revised form 16 December 2013 Accepted 30 December 2013
Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic debilitating condition that can have a severely negative impact on a patient’s quality of life. Its prevalence ranges from 52 to 500/100,000 in females compared to 8–41/100,000 in males, and its incidence is increasing globally. Treatment algorithms are sub-classified into behavioural, pharmacological, intravesical, interventional and surgical therapies. Short-term (i.e. 2% of females [1]. Early diagnosis is difficult as its clinical presentation is similar to other urogynaecological conditions, and delays in diagnosis can have a severely negative impact on a patient’s quality of life. Therefore, clinicians should be familiar with its natural history, clinical features and diagnostic criteria to facilitate appropriate and early therapy for their patients. In this narrative review we discuss the evolving epidemiology, clinical presentation and diagnostic investigations for IC/PBS. We also place particular emphasis on describing the underlying pathophysiology of the condition. As a large number of treatments have been evaluated over long periods of time for IC/PBS our final aim is to objectively investigate recommended treatment options and to discuss levels of evidence for oral, intravesical and interventional therapies (Table 1).
2. Materials and methods A literature search was undertaken using the Medline and Embase databases and the Cochrane Central Register of Controlled Trials. The following terms were entered into the search algorithm to identify peer-reviewed articles that investigated the epidemiology, clinical presentation, diagnostic investigations or treatment options for IC/PBS: ‘‘Interstitial Cystitis’’ AND ‘‘Painful Bladder Syndrome’’ OR ‘‘Interstitial Cystitis/Painful Bladder Syndrome’’. Studies on adult patients published in English between January 1957 and August 2013 were included. A manual search of the bibliographies of retrieved studies was also conducted. If a patient group was reported twice, the most recent publication was chosen. Case reports and case series with five or fewer cases were excluded. The latest search was performed on December 10th 2013. Two authors (N.F.D. and T.C.) independently examined the title and Table 1 Classification of levels of evidence based on type of research study performed. Level of evidence
Type of study
1a 1b 2a 2b 3
Meta-analysis of randomised trials At least one randomised trial One well-designed controlled study without randomisation One other type of well-designed quasi-experimental study Non-experimental study (comparative study, correlation study, case reports) Expert committee, expert opinion
4
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
31
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
35 35 35 36 36 36 36 36 36 36 36
abstract of citations and the full texts of potentially eligible articles were obtained and analysed in detail. In addition, published guidelines from the European Association of Urology (EAU) and American Urological Association (AUA) were also included in the literature search process [2–4]. Two-hundred and eleven studies published between 1938 and 2013 were retrieved, of which 44 were suitable for this narrative review, based on clinical relevance and importance of content. The epidemiology, pathophysiology, clinical features and diagnostic criteria for IC/PBS were investigated, with particular emphasis on effective treatment options. The primary data analysed included study type, sample size, type of treatment, method of administration, subjective and objective cure rates, postoperative follow-up period and any associated complications or side-effects. 3. Epidemiology Epidemiological studies on IC/PBS have demonstrated a variety of results on the prevalence of the condition. This may be due to a lack of definitive diagnostic investigations, different definitions for diagnosing IC/PBS and inaccurate sampling methodologies. Traditional evidence suggests that females are 9 times more likely to be diagnosed with IC/PBS compared to males and female gender is the only definitive risk factor for developing the condition. In a managed care population, however, the female to male ratio decreases to 5:1, which suggests that the condition may be under-diagnosed among male patients [5]. The prevalence of the condition ranges from 52 to 500/100,000 in females compared to 8–41/100,000 in males, and its incidence has been conservatively estimated at 1.2/100,000 [5]. Notably, the prevalence of IC/PBS increases to 1431/100,000 among females who have a first-degree relative with the condition and this may suggest a hereditary component for the condition. Although IC/ PBS is more frequently diagnosed in midlife, it may also present in paediatric patients and infants [6]. The prevalence of IC/PBS in the paediatric population is unknown, as the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) criteria exclude diagnosing IC/PBS in patients 6 months duration; (2) pressure/discomfort accompanied by at least one other urinary symptom such as urgency or frequency; (3) furthermore, conditions with similar presenting symptoms should be excluded with appropriate investigations before a diagnosis is made. A thorough history is important for patients presenting with pelvic discomfort, urinary frequency and urgency. Typically, patients with IC/ PBS present with pain on bladder filling that is relieved upon voiding. During the initial evaluation a voiding diary can be helpful to establish frequency and nocturia. Questionnaires such as the O’Leary–Sant interstitial cystitis symptom and problem indices reliably identify the most prominent voiding and painful symptoms in patients with IC/PBS and the extent of the perceived problem [17]. A thorough physical examination may exclude other pathologies like vaginitis, vulvar lesions, and urethral diverticulae. Relevant examination findings for IC/PBS are tenderness of the urethra and bladder base. Initial investigations should include a dipstick urinalysis and mid-stream urine (MSU) to exclude haematuria and active urinary tract infection (UTI). Importantly, patients presenting with haematuria should also undergo cystourethroscopy with cytology to rule out an underlying bladder neoplasm. A diagnostic algorithm proposed by the European Association of Urology (EAU) emphasises the importance of cystoscopy, hydrodistension and biopsy (if indicated) for accurately diagnosing IC/ PBS (Fig. 2) [18]. Rigid cystoscopy and hydrodistension also appear to be the mainstay of diagnosis among paediatric patients. The classic cystoscopic finding of an inflammatory lesion with glomerulations and/or haemorrhagic urothelial tissue was initially described by Hunner in 1914. Notably, a Hunner’s lesion can be
33
sub-classified into ulcerative and non-ulcerative variants for prognostic purposes, with the ulcerative lesion correlating with more severe pelvic pain and urinary urgency. 6. Treatment A number of treatment and management algorithms have been described and these are frequently sub-classified into behavioural, dietary, pharmacological, intravesical and interventional therapies (Fig. 2; Tables 3–5). Unfortunately, the paucity of randomised controlled trials comparing different treatment modalities has precluded the development of evidence-based management strategies and treatment protocols. In fact, the Interstitial Cystitis Data Base study noted >180 treatment modalities for IC/PBS, with poor results in the majority of cases [5]. 6.1. Conservative Behavioural therapy is beneficial for controlling symptoms such as frequency or urgency and involves times voiding, bladder training and controlled fluid intake. A reduction in overall stress levels is associated with decreased levels of pain and urgency in patients with IC/PBS. Finally, avoidance of caffeine, spicy food and carbonated drinks may have a role in decreasing the frequency of symptoms associated with IC/PBS. 6.2. Pharmacological 6.2.1. Pentosan polysulfate sodium (PPS, ELMIRON1) PPS is a synthetic sulphated polysaccharide that is used to decrease urothelial permeability by replacing defective GAGs.
Fig. 2. Flow-chart demonstrating the diagnosis and treatment options for IC/PBS [3].
34
N.F. Davis et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 175 (2014) 30–37
Table 3 Oral medications that have been investigated for the treatment of IC/PBS and their relevant levels of evidence CyA, cyclosporine A. Agent
Level of evidence
Data
Pentosan polysulfate sodium (PPS)
1a
Antidepressants
1b
Immunosuppressants
1b
Antihistamines
1b
Double-blind, placebo-controlled trial reported subjective improvement in pain, urgency and frequency in patients taking PPS compared to the control group [20] Longer durations of treatment associated with greater response rates with 50% of patients reporting an improvement after 26 week course Side effects: Gastrointestinal disturbances, headache, and fatigue; incidence ranges from 1% to 80% [22] EAU and AUA have recommended amitriptyline as a treatment option for IC/PBS Prospective randomised, double-blinded study reports greatest symptom improvement in patients that can tolerate a daily dose 50 mg [21] High rates of significant side-effects: 79–88% [21] Randomised study reported a significantly superior response rate with CyA compared to PPS (75% versus 19%, P < 0.05) [22] Recurrence of symptoms shortly after the agent is discontinued Prospective, randomised controlled trial failed to demonstrate any statistically significant improvement with hydroxyzine compared to placebo [23,24]
Table 4 Intravesical agents that have been administered for the treatment of IC/PBS and their relevant levels of evidence DMSO, dimethyl sulfoxide; BCG, Bacillus Calmette–Guerin; RTX, resinferatoxin. Agent
Level of evidence
Data
DMSO
1b
Chondroitin sulphate
2b
BCG
1b
Hyaluronon
2b
Vanilloid receptor agonists
1b
Response rates: 50–70% for a period of 1–2 months after each instillation [25] Controlled trial reported a subjective improvement in 53% of patients treated with DMSO compared to 18% in the placebo group [26] Non-randomised trial on 24 patients demonstrated improvement of 73% (range: 50–95%) [30] 1 side effect in 77% of patients [27] Prospective double-blinded study on 260 patients reported a non-significant improvement (P = 0.062) in symptoms when BCG was compared to a placebo [29] Side effects in 50% of patients [29] Pilot study demonstrated an immediate response rate of 74% with hyaluronon and hydrodistension Significant decrease in efficacy after 24 weeks Randomised double-blind placebo controlled trial of 163 patients demonstrated improvement after instillation with RTX after a 12 weeks [33,34]
Table 5 Endoscopic, minimally invasive and major surgical procedures that have been investigated for the treatment of IC/PBS and their relevant levels of evidence BoNTA, botulinum toxin A; HBO, hyperbaric oxygen. Surgical technique
Level of evidence
Data
BoNTA
1b
Cystoscopy and hydrodistension
3
Neuromodulation
3
HBO Transurethral resection Reconstructive surgery
2 N/A N/A
Prospective study on 26 patients with IC/PBS reported effective treatment in >50% of patients for 9 months [35] AUA guidelines recommend that high-pressure, long duration hydrodistension should not be offered as treatment to patients with IC/PBS due to increased frequency of perioperative adverse events [4] Retrospective study reported significant improvement in symptoms in 11/21 (52%) female patients undergoing sacral nerve stimulation after 5 years [36,37] Significant decreases in urgency and pain compared to a sham control after 12 months [38] Retrospective study describing symptomatic relief in 40% lasting >3 years [39,40] Supratrigonal cystectomy: Long-term retrospective study on 18 patients. Fourteen (78%) patients were completely pain free and 12 (67%) patients were able to void spontaneously after 5 years [41,42] Subtrigonal cystectomy: Indicated for tigonal involvement proven on biopsy and associated with more complications and poorer bladder rehabilitation Urinary diversion and ileal conduit: Most common major surgical treatment for IC/PBS
A double-blind, placebo-controlled trial demonstrated a subjective improvement in pain, urgency and frequency in patients taking PPS compared to the control group [19]. Another open multicentre trial demonstrated that PPS is more effective in classic IC/PBS compared to IC/PBS in patients without bladder lesions. Longer durations of treatment are associated with greater response rates, with approximately 50% of patients reporting an improvement in their symptoms after a 26-week course of therapy [20]. Side effects from oral PPS are gastrointestinal disturbances, headache, and fatigue, and their incidence ranges from 1% to 80%. 6.2.2. Antidepressants EAU guidelines on chronic pelvic pain and AUA Guidelines for the treatment of IC/PBS have recommended amitriptyline as a treatment option for IC/PBS [4]. Amitriptyline blocks H1-histaminergic receptors and decreases mast cell activity. In addition,
amitriptyline decreases painful nociception by inhibiting synaptic reuptake of serotonin and norepinephrine. It appears that the agent is most beneficial with stepwise dose escalation, with one prospective randomised, double-blinded study demonstrating the greatest symptom improvement in patients that can tolerate a daily dose 50 mg. Importantly, amitriptyline is associated with high rates of significant side-effects, with symptoms such as dry mouth, dizziness and gastrointestinal problems occurring in 79– 88% of patients compared to 21–72% of patients treated with placebo [21]. Other potentially useful tricyclic anti-depressants are doxepin and desipramine, but there is a paucity of available data on their efficacy. 6.2.3. Immunosuppressant therapy Cyclosporin A (CyA) has shown potential for the treatment of IC/ PBS, as demonstrated in one randomised study where the agent
N.F. Davis et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 175 (2014) 30–37
was compared with PPS in 64 patients [22]. Dose regimens were 1.5 mg/kg for CyA twice daily versus low-dose PPS for 6 months and results demonstrated a significantly superior response rate with CyA (75% versus 19%, P < 0.05). Disadvantages of CyA in this setting are more frequent side-effects (hypertension and increased serum creatinine) and recurrence of symptoms shortly after the agent is discontinued. Other possible immunosuppressive agents for IC/PBS are azathioprine and methotrexate but there is a paucity of prospective data on their therapeutic potential. Notably, guidelines from the AUA recommend that oral long-term glucocorticoid therapy should not be offered as treatment in patients with IC/PBS [4]. 6.2.4. Antihistamines Hydroxyzine is a histamine receptor antagonist that blocks the H1-receptor subtypes and inhibits the activation of mast cells. Hydroxyzine hydrochloride (Atarax1) is administered with the potential for dose escalation up to 75 mg, and early studies reported an improvement in >90% of patients on this medication. Notably, a more recent prospective, randomised controlled trial failed to demonstrate any statistically significant improvement with hydroxyzine compared to a placebo [23]. Cimetidine is an H2receptor antagonist and perhaps offers greater potential compared to hydroxyzine. One early pilot study of 31 patients reported symptomatic relief in 71% of patients with a dosage of 200 mg three times daily, and these results have been substantiated with a follow-up randomised controlled trial where the agent significantly reduced the incidence of suprapubic pain and nocturia (P = 0.009 and P = 0.006, respectively) in 34 patients after a 3month follow-up period [24]. 6.3. Intravesical Advantages of an intravesical approach for introducing medical therapy are the potential for high concentrations of therapeutic agents and decreased potential for systemic side-effects. Disadvantages of this approach are its invasiveness, risk of infection and costly nature. A number of intravesical treatments have been investigated for the treatment of IC/PBS as described below (Table 4): 6.3.1. Dimethyl sulfoxide (DMSO) DMSO is a water-soluble, collagenolytic, anti-inflammatory chemical solvent with analgesic and muscle relaxant properties. Although its mechanism of action is poorly understood; its role in treating IC/PBS is long-standing due to its ability to alleviate pain and urgency. Response rates range from 50% to 70% for a period of 1–2 months after each instillation [25]. One early controlled trial compared the effectiveness of intravesical DMSO with a placebo in 33 patients with IC/PBS and reported a subjective improvement in 53% of patients treated with DMSO, compared to 18% in the placebo group [26]. 6.3.2. Chondroitin sulphate GAG replacement therapy with chondroitin sulphate has shown promising early results for the treatment of IC/PBS. One nonrandomised trial on 24 patients with refractory IC/PBS demonstrated an average symptom score improvement of 73% (range 50– 95%) in 20 patients after intravesical treatment with chondroitin sulphate. Patients underwent instillations with 2% chondroitin sulphate twice weekly for 2 weeks followed by once weekly with 0.2% for 4 weeks and monthly thereafter for 1 year. Another nonrandomised trial demonstrated an improvement in 92% (n = 12/13) of patients treated with intravesical chondroitin sulphate for 13 months [27]. In this study, patients underwent weekly instillations of 40 ml for 4 weeks followed by monthly instillations thereafter.
35
An important limitation with these studies is their relatively small sample size. In addition, intravesical chondroitin sulphate is associated with at least one side effect (e.g. dysuria, nausea, gastrointestinal upset, macular rash and urethritis) in 77% of patients [28]. 6.3.3. Bacillus Calmette–Guerin (BCG) Although BCG demonstrated response rates of 60% for the treatment of IC/PBS in the 1990s, its efficacy has recently been questioned. A subsequent prospective, double blind trial comparing BCG and DMSO failed to demonstrate any benefit with BCG [29]. Furthermore, significant irritative symptoms occur in approximately 50% of patients undergoing treatment with BCG therapy and the AUA recommend that BCG should not be offered as a treatment option for IC/PBS except in the setting of approved investigational studies [4]. 6.3.4. Hyaluronon Hyaluronon or hyaluronic acid is a non-sulphated GAG with short-term efficacy for treating IC/PBS [30]. Response rates are in the region of 53–56% 4 weeks after intravesical administration [30]. Interestingly, response rates can increase to 70% after 7 weeks, as demonstrated in one small study of 25 patients undergoing treatment with intravesical hyaluronon [31]. Another pilot study demonstrated an immediate response rate of 74% in patients undergoing treatment with intravesical hyaluronon after hydrodistension [32]. A limitation with this treatment modality is a significant decrease in efficacy after 24 weeks, but side-effects occur infrequently. 6.3.5. Vaniloid receptor agonists Resinferatoxin (RTX) is a potent analogue of capsaicin that desensitises C-fibres, which transmit pain. Although efficacy was demonstrated in small clinical trials, a randomised multicentre study failed to demonstrate any advantage compared to a placebo [33]. Another randomised double-blind placebo-controlled trial of 163 patients demonstrated no symptomatic improvement after intravesical instillation of RTX after a 12 week follow-up period, and AUA guidelines recommend that RTX should not be offered as treatment for IC/PBS [4,34]. 6.4. Interventional procedures 6.4.1. Botulinum toxin A (BoNTA) BoNTA has shown recent promise as a minimally invasive treatment option for IC/PBS. One prospective study recently evaluated trigonal injection of BoNTA as a treatment option for refractory IC/PBS in 26 female patients [35]. After 3 months all patients reported an improvement in their symptoms, and treatment remained effective in >50% of patients for 9 months [35]. Although the initial results with BoNTA as a reliable treatment option for refractory IC/PBS are promising, additional prospective studies will be required before its true efficacy can be clearly established. 6.4.2. Cystoscopy and hydrodistension Although hydrodistension has been used in the treatment of refractory IC/PBS for a number of years, recent data demonstrate poor long-term results with regard to symptomatic improvement. Furthermore, guidelines from the AUA recommend that highpressure, long duration hydrodistension should not be offered to patients with IC/PBS due to its inconsistent nature and increased frequency of perioperative adverse events [4]. These findings suggest that hydrodistension represents a useful diagnostic modality but remains severely limited as a reliable treatment option for IC/PBS. Diagnosis with hydrodistension includes
N.F. Davis et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 175 (2014) 30–37
36
inspection of the bladder with accurate grading of any lesions that are present:
Grade Grade Grade Grade
0: 1: 2: 3:
Normal mucosa. Petechiae in at least two quadrants. Large submucosal bleeding. Diffuse global mucosal bleeding.
6.4.3. Neuromodulation There is a paucity of available data on neuromodulation with sacral nerve stimulation and it still remains an investigational treatment option. One short-term study on 30 patients undergoing bilateral caudal epidural sacral neuromodulation for the treatment of refractory IC/PBS reported a 42% improvement in symptoms 6 months postoperatively [36]. Another more recent retrospective study demonstrated a significant improvement in suprapubic and voiding parameters in 11/21 (52%) female patients undergoing sacral nerve stimulation after 5 years of follow-up [37]. 6.4.4. Hyperbaric oxygen (HBO) HBO therapy has demonstrated significant advantages compared to a sham control for the treatment of IC/PBS after 12 months [38]. Specifically, HBO is associated with decreases in urgency and pain, but limited availability and high costs are likely to delay its progression clinically. 6.5. Surgical therapy Invasive surgical procedures are usually reserved for patients who remain refractory to conservative therapies. Pre-operatively, patients should be counselled thoroughly on the definitive nature and potential side-effects of the procedure (Table 5) 6.5.1. Transurethral resection and coagulation Hunner’s lesions can be endoscopically ablated for symptomatic relief. One early non-randomised study reported on 77 patients with Hunner’s lesions that were managed conservatively (n = 42), with fulgaration (n = 7) or with transurethral resection (n = 28). Although all patients undergoing surgical therapy experienced short-term symptomatic improvement, efficacy was not significantly superior to conservative management at 12 months [39]. Encouragingly, a more recent retrospective study evaluated the long-term outcomes of 259 transurethral resections on 103 symptomatic patients [40]. Ninety-two patients reported amelioration of their symptoms, with 40% describing symptomatic relief lasting >3 years. The authors conclude by suggesting that transurethral resection should be offered as first-line treatment for patients with classic features of IC/PBS. 6.5.2. Major surgical procedures There are three major surgical techniques for the treatment of refractory IC/PBS and each technique usually necessitates substitution of bladder tissue with a segment of bowel: (1) supratrigonal cystectomy; (2) subtrigonal cystectomy; and (3) urinary diversion radical cystectomy and urethrectomy. Supratrigonal cystectomy and enterocystoplasty represents the most favourable continence preserving technique. A number of gastrointestinal segments have been applied for trigonal augmentation, such as ileum, ileocaecum, ascending colon and sigmoid colon. Gastric tissue, however, appears less effective due to persistent production of gastric acids with resultant dysuria and suprapubic pain. Long-term results are encouraging, as described in one study on 18 patients who were followed up for 5 years [41]. Fourteen (78%) patients were completely pain free and 12 (67%) patients were able to void spontaneously. Importantly, persistent
frequency and reduced bladder capacity due to active disease in the remaining trigone and/or urethra have been reported in up to 30% of patients undergoing supratrigonal cystectomy [42]. Subtrigonal cystectomy is associated with more complications and poorer bladder rehabilitation, as the procedure typically requires ureteral reimplantation with associated risks of leakage, stricture, and reflux [43]. Indications for subtrigonal cystectomy are patients with refractory IC/PBS and biopsy proven trigonal involvement. Post-operative self-intermittent catheterisation (SIC), sexual dysfunction and voiding difficulties are more common in this patient cohort as demonstrated by Volkmer et al. in one study on eight female patients where only one patient regained normal sexual activity after undergoing subtrigonal cystectomy for IC/PBS [44]. Intuitively, urinary diversion with/without radical cystectomy is the most invasive surgical treatment option. Indications include biopsy proven involvement of the trigone (with a highly sensate urethra) and in patients unwilling or unable to perform intermittent self-catheterisation post-operatively. Simple urinary diversion with the formation of an ileal conduit is the most common surgical treatment for IC/PBS and is particularly recommended for patients with recurrent pain in the augmented bladder or continent pouch after enterocystoplasty or continent urinary diversion. 7. Conclusions Our analysis suggests that IC/PBS is under-diagnosed among the general population. Clinicians are likely to experience increasing numbers of patients with the condition as more is understood about its pathophysiology and evolving epidemiology. Therefore, urogynaecologists should sufficiently familiarise themselves with appropriate diagnostic criteria and evidence based therapies for IC/ PBS if clinical outcomes in this complex patient cohort are to improve in the near future. Financial disclosures None. Condensation Urogynaecologists should familiarise themselves with appropriate diagnostic criteria and evidence-based therapies for interstitial cystitis/painful bladder syndrome to optimise clinical outcomes in these patients. Acknowledgements None. References [1] Clemens JQ, Link CL, Eggers PW, et al. Prevalence of painful bladder symptoms and effect on quality of life in black, Hispanic and white men and women. J Urol 2007;177:1390–4. [2] Engeler DS, Baranowski AP, Dinis-Oliveira P, et al. The 2013 EAU guidelines on chronic pelvic pain: is management of chronic pelvic pain a habit, a philosophy, or a science? 10 years of development. Eur Urol 2013;64:431–9. [3] Fall M, Baranowski AP, Elneil S, et al. EAU guidelines on chronic pelvic pain. Eur Urol 2010;57:35–48. [4] Hanno PM, Burks DA, Clemens JQ, et al. AUA guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. J Urol 2011;185:2162–70. [5] Clemens JQ, Meenan RT, Rosetti MC, Gao SY, Calhoun EA. Prevalence and incidence of interstitial cystitis in a managed care population. J Urol 2005;173:98–102. discussion. [6] Park JM. Is interstitial cystitis an underdiagnosed problem in children? A diagnostic and therapeutic dilemma. Urology 2001;57(6 Suppl 1):30–1. [7] Davis NF, Breslin N, Creagh T. Using google trends to assess global interest in ‘dysport(R)’ for the treatment of overactive bladder. Urology 2013;82:1189.
N.F. Davis et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 175 (2014) 30–37 [8] Davis NF, Smyth LG, Flood HD. Detecting internet activity for erectile dysfunction using search engine query data in the Republic of Ireland. BJU Int 2012;110:E939–42. [9] Keay S, Seillier-Moiseiwitsch F, Zhang CO, Chai TC, Zhang J. Changes in human bladder epithelial cell gene expression associated with interstitial cystitis or antiproliferative factor treatment. Physiol Genomics 2003;14:107–15. [10] Vij M, Srikrishna S, Cardozo L. Interstitial cystitis: diagnosis and management. Eur J Obstet Gynecol Reprod Biol 2012;161:1–7. [11] Davis NF, McGuire BB, Callanan A, Flood HD, McGloughlin TM. Xenogenic extracellular matrices as potential biomaterials for interposition grafting in urological surgery. J Urol 2010;184:2246–53. [12] Parsons CL. The role of the urinary epithelium in the pathogenesis of interstitial cystitis/prostatitis/urethritis. Urology 2007;69(4 Suppl):9–16. [13] Lokeshwar VB, Selzer MG, Cerwinka WH, et al. Urinary uronate and sulfated glycosaminoglycan levels: markers for interstitial cystitis severity. J Urol 2005;174:344–9. [14] Smith SD, Wheeler MA, Foster Jr HE, Weiss RM. Urinary nitric oxide synthase activity and cyclic GMP levels are decreased with interstitial cystitis and increased with urinary tract infections. J Urol 1996;155:1432–5. [15] Silk MR. Bladder antibodies in interstitial cystitis. J Urol 1970;103:307–9. [16] Warren JW, Jackson TL, Langenberg P, Meyers DJ, Xu J. Prevalence of interstitial cystitis in first-degree relatives of patients with interstitial cystitis. Urology 2004;63:17–21. [17] Lubeck DP, Whitmore K, Sant GR, Alvarez-Horine S, Lai C. Psychometric validation of the O’leary–Sant interstitial cystitis symptom index in a clinical trial of pentosan polysulfate sodium. Urology 2001;57(6 Suppl 1):62–6. [18] van de Merwe JP, Nordling J, Bouchelouche P, et al. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal. Eur Urol 2008;53:60–7. [19] Mulholland SG, Hanno P, Parsons CL, Sant GR, Staskin DR. Pentosan polysulfate sodium for therapy of interstitial cystitis. A double-blind placebo-controlled clinical study. Urology 1990;35:552–8. [20] Nickel JC, Barkin J, Forrest J, et al. Randomized, double-blind, dose-ranging study of pentosan polysulfate sodium for interstitial cystitis. Urology 2005;65:654–8. [21] van Ophoven A, Pokupic S, Heinecke A, Hertle L. A prospective, randomized, placebo controlled, double-blind study of amitriptyline for the treatment of interstitial cystitis. J Urol 2004;172:533–6. [22] Sairanen J, Tammela TL, Leppilahti M, et al. Cyclosporine A and pentosan polysulfate sodium for the treatment of interstitial cystitis: a randomized comparative study. J Urol 2005;174:2235–8. [23] Sant GR, Propert KJ, Hanno PM, et al. A pilot clinical trial of oral pentosan polysulfate and oral hydroxyzine in patients with interstitial cystitis. J Urol 2003;170:810–5. [24] Thilagarajah R, Witherow RO, Walker MM. Oral cimetidine gives effective symptom relief in painful bladder disease: a prospective, randomized, doubleblind placebo-controlled trial. BJU Int 2001;87:207–12. [25] Sant GR, LaRock DR. Standard intravesical therapies for interstitial cystitis. Urol Clin North Am 1994;21:73–83. [26] Perez-Marrero R, Emerson LE, Feltis JT. A controlled study of dimethyl sulfoxide in interstitial cystitis. J Urol 1988;140:36–9. [27] Steinhoff G, Ittah B, Rowan S. The efficacy of chondroitin sulfate 0.2% in treating interstitial cystitis. Can J Urol 2002;9:1454–8.
37
[28] Nickel JC, Egerdie RB, Steinhoff G, Palmer B, Hanno P. A multicenter, randomized, double-blind, parallel group pilot evaluation of the efficacy and safety of intravesical sodium chondroitin sulfate versus vehicle control in patients with interstitial cystitis/painful bladder syndrome. Urology 2010;76:804–9. [29] Peeker R, Haghsheno MA, Holmang S, Fall M. Intravesical bacillus Calmette– Guerin and dimethyl sulfoxide for treatment of classic and nonulcer interstitial cystitis: a prospective, randomized double-blind study. J Urol 2000;164:1912–5. discussion 5–6. [30] Riedl CR, Engelhardt PF, Daha KL, Morakis N, Pfluger H. Hyaluronan treatment of interstitial cystitis/painful bladder syndrome. Int Urogynecol J Pelvic Floor Dysfunct 2008;19:717–21. [31] Morales A, Emerson L, Nickel JC. Intravesical hyaluronic acid in the treatment of refractory interstitial cystitis. Urology 1997;49(5A Suppl):111–3. [32] Ahmad I. Sarath Krishna N, Meddings RN. Sequential hydrodistension and intravesical instillation of hyaluronic acid under general anaesthesia for treatment of refractory interstitial cystitis: a pilot study. Int Urogynecol J Pelvic Floor Dysfunct 2008;19:543–6. [33] Apostolidis A, Gonzales GE, Fowler CJ. Effect of intravesical Resiniferatoxin (RTX) on lower urinary tract symptoms, urodynamic parameters, and quality of life of patients with urodynamic increased bladder sensation. Eur Urol 2006;50:1299–305. [34] Payne CK, Mosbaugh PG, Forrest JB, et al. Intravesical resiniferatoxin for the treatment of interstitial cystitis: a randomized, double-blind, placebo controlled trial. J Urol 2005;173:1590–4. [35] Pinto R, Lopes T, Frias B, et al. Trigonal injection of botulinum toxin A in patients with refractory bladder pain syndrome/interstitial cystitis. Eur Urol 2010;58:360–5. [36] Zabihi N, Mourtzinos A, Maher MG, Raz S, Rodriguez LV. Short-term results of bilateral S2–S4 sacral neuromodulation for the treatment of refractory interstitial cystitis, painful bladder syndrome, and chronic pelvic pain. Int Urogynecol J Pelvic Floor Dysfunct 2008;19:553–7. [37] Ghazwani YQ, Elkelini MS, Hassouna MM. Efficacy of sacral neuromodulation in treatment of bladder pain syndrome: long-term follow-up. Neurourol Urodyn 2011;30:1271–5. [38] van Ophoven A, Rossbach G, Pajonk F, Hertle L. Safety and efficacy of hyperbaric oxygen therapy for the treatment of interstitial cystitis: a randomized, sham controlled, double-blind trial. J Urol 2006;176:1442–6. [39] Greenberg E, Barnes R, Stewart S, Furnish T. Transurethral resection of Hunner’s ulcer. J Urol 1974;111:764–6. [40] Peeker R, Aldenborg F, Fall M. Complete transurethral resection of ulcers in classic interstitial cystitis. Int Urogynecol J Pelvic Floor Dysfunct 2000;11:290–5. [41] van Ophoven A, Oberpenning F, Hertle L. Long-term results of trigone-preserving orthotopic substitution enterocystoplasty for interstitial cystitis. J Urol 2002;167:603–7. [42] Blaivas JG, Weiss JP, Desai P, Flisser AJ, Stember DS, Stahl PJ. Long-term followup of augmentation enterocystoplasty and continent diversion in patients with benign disease. J Urol 2005;173:1631–4. [43] Fall M, Oberpenning F, Peeker R. Treatment of bladder pain syndrome/interstitial cystitis 2008: can we make evidence-based decisions. Eur Urol 2008;54:65–75. [44] Volkmer BG, Gschwend JE, Herkommer K, Simon J, Kufer R, Hautmann RE. Cystectomy and orthotopic ileal neobladder: the impact on female sexuality. J Urol 2004;172:2353–7.
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Review
Interstitial cystitis/painful bladder syndrome: epidemiology, pathophysiology and evidence-based treatment options N.F. Davis a,b,*, C.M. Brady b, T. Creagh a a b
Department of Urogynaecology, Beaumont Hospital, Dublin, Ireland Department of Urology, Cork University Hospital, Cork, Ireland
A R T I C L E I N F O
A B S T R A C T
Article history: Received 18 August 2013 Received in revised form 16 December 2013 Accepted 30 December 2013
Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic debilitating condition that can have a severely negative impact on a patient’s quality of life. Its prevalence ranges from 52 to 500/100,000 in females compared to 8–41/100,000 in males, and its incidence is increasing globally. Treatment algorithms are sub-classified into behavioural, pharmacological, intravesical, interventional and surgical therapies. Short-term (i.e. 2% of females [1]. Early diagnosis is difficult as its clinical presentation is similar to other urogynaecological conditions, and delays in diagnosis can have a severely negative impact on a patient’s quality of life. Therefore, clinicians should be familiar with its natural history, clinical features and diagnostic criteria to facilitate appropriate and early therapy for their patients. In this narrative review we discuss the evolving epidemiology, clinical presentation and diagnostic investigations for IC/PBS. We also place particular emphasis on describing the underlying pathophysiology of the condition. As a large number of treatments have been evaluated over long periods of time for IC/PBS our final aim is to objectively investigate recommended treatment options and to discuss levels of evidence for oral, intravesical and interventional therapies (Table 1).
2. Materials and methods A literature search was undertaken using the Medline and Embase databases and the Cochrane Central Register of Controlled Trials. The following terms were entered into the search algorithm to identify peer-reviewed articles that investigated the epidemiology, clinical presentation, diagnostic investigations or treatment options for IC/PBS: ‘‘Interstitial Cystitis’’ AND ‘‘Painful Bladder Syndrome’’ OR ‘‘Interstitial Cystitis/Painful Bladder Syndrome’’. Studies on adult patients published in English between January 1957 and August 2013 were included. A manual search of the bibliographies of retrieved studies was also conducted. If a patient group was reported twice, the most recent publication was chosen. Case reports and case series with five or fewer cases were excluded. The latest search was performed on December 10th 2013. Two authors (N.F.D. and T.C.) independently examined the title and Table 1 Classification of levels of evidence based on type of research study performed. Level of evidence
Type of study
1a 1b 2a 2b 3
Meta-analysis of randomised trials At least one randomised trial One well-designed controlled study without randomisation One other type of well-designed quasi-experimental study Non-experimental study (comparative study, correlation study, case reports) Expert committee, expert opinion
4
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
31
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
35 35 35 36 36 36 36 36 36 36 36
abstract of citations and the full texts of potentially eligible articles were obtained and analysed in detail. In addition, published guidelines from the European Association of Urology (EAU) and American Urological Association (AUA) were also included in the literature search process [2–4]. Two-hundred and eleven studies published between 1938 and 2013 were retrieved, of which 44 were suitable for this narrative review, based on clinical relevance and importance of content. The epidemiology, pathophysiology, clinical features and diagnostic criteria for IC/PBS were investigated, with particular emphasis on effective treatment options. The primary data analysed included study type, sample size, type of treatment, method of administration, subjective and objective cure rates, postoperative follow-up period and any associated complications or side-effects. 3. Epidemiology Epidemiological studies on IC/PBS have demonstrated a variety of results on the prevalence of the condition. This may be due to a lack of definitive diagnostic investigations, different definitions for diagnosing IC/PBS and inaccurate sampling methodologies. Traditional evidence suggests that females are 9 times more likely to be diagnosed with IC/PBS compared to males and female gender is the only definitive risk factor for developing the condition. In a managed care population, however, the female to male ratio decreases to 5:1, which suggests that the condition may be under-diagnosed among male patients [5]. The prevalence of the condition ranges from 52 to 500/100,000 in females compared to 8–41/100,000 in males, and its incidence has been conservatively estimated at 1.2/100,000 [5]. Notably, the prevalence of IC/PBS increases to 1431/100,000 among females who have a first-degree relative with the condition and this may suggest a hereditary component for the condition. Although IC/ PBS is more frequently diagnosed in midlife, it may also present in paediatric patients and infants [6]. The prevalence of IC/PBS in the paediatric population is unknown, as the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) criteria exclude diagnosing IC/PBS in patients 6 months duration; (2) pressure/discomfort accompanied by at least one other urinary symptom such as urgency or frequency; (3) furthermore, conditions with similar presenting symptoms should be excluded with appropriate investigations before a diagnosis is made. A thorough history is important for patients presenting with pelvic discomfort, urinary frequency and urgency. Typically, patients with IC/ PBS present with pain on bladder filling that is relieved upon voiding. During the initial evaluation a voiding diary can be helpful to establish frequency and nocturia. Questionnaires such as the O’Leary–Sant interstitial cystitis symptom and problem indices reliably identify the most prominent voiding and painful symptoms in patients with IC/PBS and the extent of the perceived problem [17]. A thorough physical examination may exclude other pathologies like vaginitis, vulvar lesions, and urethral diverticulae. Relevant examination findings for IC/PBS are tenderness of the urethra and bladder base. Initial investigations should include a dipstick urinalysis and mid-stream urine (MSU) to exclude haematuria and active urinary tract infection (UTI). Importantly, patients presenting with haematuria should also undergo cystourethroscopy with cytology to rule out an underlying bladder neoplasm. A diagnostic algorithm proposed by the European Association of Urology (EAU) emphasises the importance of cystoscopy, hydrodistension and biopsy (if indicated) for accurately diagnosing IC/ PBS (Fig. 2) [18]. Rigid cystoscopy and hydrodistension also appear to be the mainstay of diagnosis among paediatric patients. The classic cystoscopic finding of an inflammatory lesion with glomerulations and/or haemorrhagic urothelial tissue was initially described by Hunner in 1914. Notably, a Hunner’s lesion can be
33
sub-classified into ulcerative and non-ulcerative variants for prognostic purposes, with the ulcerative lesion correlating with more severe pelvic pain and urinary urgency. 6. Treatment A number of treatment and management algorithms have been described and these are frequently sub-classified into behavioural, dietary, pharmacological, intravesical and interventional therapies (Fig. 2; Tables 3–5). Unfortunately, the paucity of randomised controlled trials comparing different treatment modalities has precluded the development of evidence-based management strategies and treatment protocols. In fact, the Interstitial Cystitis Data Base study noted >180 treatment modalities for IC/PBS, with poor results in the majority of cases [5]. 6.1. Conservative Behavioural therapy is beneficial for controlling symptoms such as frequency or urgency and involves times voiding, bladder training and controlled fluid intake. A reduction in overall stress levels is associated with decreased levels of pain and urgency in patients with IC/PBS. Finally, avoidance of caffeine, spicy food and carbonated drinks may have a role in decreasing the frequency of symptoms associated with IC/PBS. 6.2. Pharmacological 6.2.1. Pentosan polysulfate sodium (PPS, ELMIRON1) PPS is a synthetic sulphated polysaccharide that is used to decrease urothelial permeability by replacing defective GAGs.
Fig. 2. Flow-chart demonstrating the diagnosis and treatment options for IC/PBS [3].
34
N.F. Davis et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 175 (2014) 30–37
Table 3 Oral medications that have been investigated for the treatment of IC/PBS and their relevant levels of evidence CyA, cyclosporine A. Agent
Level of evidence
Data
Pentosan polysulfate sodium (PPS)
1a
Antidepressants
1b
Immunosuppressants
1b
Antihistamines
1b
Double-blind, placebo-controlled trial reported subjective improvement in pain, urgency and frequency in patients taking PPS compared to the control group [20] Longer durations of treatment associated with greater response rates with 50% of patients reporting an improvement after 26 week course Side effects: Gastrointestinal disturbances, headache, and fatigue; incidence ranges from 1% to 80% [22] EAU and AUA have recommended amitriptyline as a treatment option for IC/PBS Prospective randomised, double-blinded study reports greatest symptom improvement in patients that can tolerate a daily dose 50 mg [21] High rates of significant side-effects: 79–88% [21] Randomised study reported a significantly superior response rate with CyA compared to PPS (75% versus 19%, P < 0.05) [22] Recurrence of symptoms shortly after the agent is discontinued Prospective, randomised controlled trial failed to demonstrate any statistically significant improvement with hydroxyzine compared to placebo [23,24]
Table 4 Intravesical agents that have been administered for the treatment of IC/PBS and their relevant levels of evidence DMSO, dimethyl sulfoxide; BCG, Bacillus Calmette–Guerin; RTX, resinferatoxin. Agent
Level of evidence
Data
DMSO
1b
Chondroitin sulphate
2b
BCG
1b
Hyaluronon
2b
Vanilloid receptor agonists
1b
Response rates: 50–70% for a period of 1–2 months after each instillation [25] Controlled trial reported a subjective improvement in 53% of patients treated with DMSO compared to 18% in the placebo group [26] Non-randomised trial on 24 patients demonstrated improvement of 73% (range: 50–95%) [30] 1 side effect in 77% of patients [27] Prospective double-blinded study on 260 patients reported a non-significant improvement (P = 0.062) in symptoms when BCG was compared to a placebo [29] Side effects in 50% of patients [29] Pilot study demonstrated an immediate response rate of 74% with hyaluronon and hydrodistension Significant decrease in efficacy after 24 weeks Randomised double-blind placebo controlled trial of 163 patients demonstrated improvement after instillation with RTX after a 12 weeks [33,34]
Table 5 Endoscopic, minimally invasive and major surgical procedures that have been investigated for the treatment of IC/PBS and their relevant levels of evidence BoNTA, botulinum toxin A; HBO, hyperbaric oxygen. Surgical technique
Level of evidence
Data
BoNTA
1b
Cystoscopy and hydrodistension
3
Neuromodulation
3
HBO Transurethral resection Reconstructive surgery
2 N/A N/A
Prospective study on 26 patients with IC/PBS reported effective treatment in >50% of patients for 9 months [35] AUA guidelines recommend that high-pressure, long duration hydrodistension should not be offered as treatment to patients with IC/PBS due to increased frequency of perioperative adverse events [4] Retrospective study reported significant improvement in symptoms in 11/21 (52%) female patients undergoing sacral nerve stimulation after 5 years [36,37] Significant decreases in urgency and pain compared to a sham control after 12 months [38] Retrospective study describing symptomatic relief in 40% lasting >3 years [39,40] Supratrigonal cystectomy: Long-term retrospective study on 18 patients. Fourteen (78%) patients were completely pain free and 12 (67%) patients were able to void spontaneously after 5 years [41,42] Subtrigonal cystectomy: Indicated for tigonal involvement proven on biopsy and associated with more complications and poorer bladder rehabilitation Urinary diversion and ileal conduit: Most common major surgical treatment for IC/PBS
A double-blind, placebo-controlled trial demonstrated a subjective improvement in pain, urgency and frequency in patients taking PPS compared to the control group [19]. Another open multicentre trial demonstrated that PPS is more effective in classic IC/PBS compared to IC/PBS in patients without bladder lesions. Longer durations of treatment are associated with greater response rates, with approximately 50% of patients reporting an improvement in their symptoms after a 26-week course of therapy [20]. Side effects from oral PPS are gastrointestinal disturbances, headache, and fatigue, and their incidence ranges from 1% to 80%. 6.2.2. Antidepressants EAU guidelines on chronic pelvic pain and AUA Guidelines for the treatment of IC/PBS have recommended amitriptyline as a treatment option for IC/PBS [4]. Amitriptyline blocks H1-histaminergic receptors and decreases mast cell activity. In addition,
amitriptyline decreases painful nociception by inhibiting synaptic reuptake of serotonin and norepinephrine. It appears that the agent is most beneficial with stepwise dose escalation, with one prospective randomised, double-blinded study demonstrating the greatest symptom improvement in patients that can tolerate a daily dose 50 mg. Importantly, amitriptyline is associated with high rates of significant side-effects, with symptoms such as dry mouth, dizziness and gastrointestinal problems occurring in 79– 88% of patients compared to 21–72% of patients treated with placebo [21]. Other potentially useful tricyclic anti-depressants are doxepin and desipramine, but there is a paucity of available data on their efficacy. 6.2.3. Immunosuppressant therapy Cyclosporin A (CyA) has shown potential for the treatment of IC/ PBS, as demonstrated in one randomised study where the agent
N.F. Davis et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 175 (2014) 30–37
was compared with PPS in 64 patients [22]. Dose regimens were 1.5 mg/kg for CyA twice daily versus low-dose PPS for 6 months and results demonstrated a significantly superior response rate with CyA (75% versus 19%, P < 0.05). Disadvantages of CyA in this setting are more frequent side-effects (hypertension and increased serum creatinine) and recurrence of symptoms shortly after the agent is discontinued. Other possible immunosuppressive agents for IC/PBS are azathioprine and methotrexate but there is a paucity of prospective data on their therapeutic potential. Notably, guidelines from the AUA recommend that oral long-term glucocorticoid therapy should not be offered as treatment in patients with IC/PBS [4]. 6.2.4. Antihistamines Hydroxyzine is a histamine receptor antagonist that blocks the H1-receptor subtypes and inhibits the activation of mast cells. Hydroxyzine hydrochloride (Atarax1) is administered with the potential for dose escalation up to 75 mg, and early studies reported an improvement in >90% of patients on this medication. Notably, a more recent prospective, randomised controlled trial failed to demonstrate any statistically significant improvement with hydroxyzine compared to a placebo [23]. Cimetidine is an H2receptor antagonist and perhaps offers greater potential compared to hydroxyzine. One early pilot study of 31 patients reported symptomatic relief in 71% of patients with a dosage of 200 mg three times daily, and these results have been substantiated with a follow-up randomised controlled trial where the agent significantly reduced the incidence of suprapubic pain and nocturia (P = 0.009 and P = 0.006, respectively) in 34 patients after a 3month follow-up period [24]. 6.3. Intravesical Advantages of an intravesical approach for introducing medical therapy are the potential for high concentrations of therapeutic agents and decreased potential for systemic side-effects. Disadvantages of this approach are its invasiveness, risk of infection and costly nature. A number of intravesical treatments have been investigated for the treatment of IC/PBS as described below (Table 4): 6.3.1. Dimethyl sulfoxide (DMSO) DMSO is a water-soluble, collagenolytic, anti-inflammatory chemical solvent with analgesic and muscle relaxant properties. Although its mechanism of action is poorly understood; its role in treating IC/PBS is long-standing due to its ability to alleviate pain and urgency. Response rates range from 50% to 70% for a period of 1–2 months after each instillation [25]. One early controlled trial compared the effectiveness of intravesical DMSO with a placebo in 33 patients with IC/PBS and reported a subjective improvement in 53% of patients treated with DMSO, compared to 18% in the placebo group [26]. 6.3.2. Chondroitin sulphate GAG replacement therapy with chondroitin sulphate has shown promising early results for the treatment of IC/PBS. One nonrandomised trial on 24 patients with refractory IC/PBS demonstrated an average symptom score improvement of 73% (range 50– 95%) in 20 patients after intravesical treatment with chondroitin sulphate. Patients underwent instillations with 2% chondroitin sulphate twice weekly for 2 weeks followed by once weekly with 0.2% for 4 weeks and monthly thereafter for 1 year. Another nonrandomised trial demonstrated an improvement in 92% (n = 12/13) of patients treated with intravesical chondroitin sulphate for 13 months [27]. In this study, patients underwent weekly instillations of 40 ml for 4 weeks followed by monthly instillations thereafter.
35
An important limitation with these studies is their relatively small sample size. In addition, intravesical chondroitin sulphate is associated with at least one side effect (e.g. dysuria, nausea, gastrointestinal upset, macular rash and urethritis) in 77% of patients [28]. 6.3.3. Bacillus Calmette–Guerin (BCG) Although BCG demonstrated response rates of 60% for the treatment of IC/PBS in the 1990s, its efficacy has recently been questioned. A subsequent prospective, double blind trial comparing BCG and DMSO failed to demonstrate any benefit with BCG [29]. Furthermore, significant irritative symptoms occur in approximately 50% of patients undergoing treatment with BCG therapy and the AUA recommend that BCG should not be offered as a treatment option for IC/PBS except in the setting of approved investigational studies [4]. 6.3.4. Hyaluronon Hyaluronon or hyaluronic acid is a non-sulphated GAG with short-term efficacy for treating IC/PBS [30]. Response rates are in the region of 53–56% 4 weeks after intravesical administration [30]. Interestingly, response rates can increase to 70% after 7 weeks, as demonstrated in one small study of 25 patients undergoing treatment with intravesical hyaluronon [31]. Another pilot study demonstrated an immediate response rate of 74% in patients undergoing treatment with intravesical hyaluronon after hydrodistension [32]. A limitation with this treatment modality is a significant decrease in efficacy after 24 weeks, but side-effects occur infrequently. 6.3.5. Vaniloid receptor agonists Resinferatoxin (RTX) is a potent analogue of capsaicin that desensitises C-fibres, which transmit pain. Although efficacy was demonstrated in small clinical trials, a randomised multicentre study failed to demonstrate any advantage compared to a placebo [33]. Another randomised double-blind placebo-controlled trial of 163 patients demonstrated no symptomatic improvement after intravesical instillation of RTX after a 12 week follow-up period, and AUA guidelines recommend that RTX should not be offered as treatment for IC/PBS [4,34]. 6.4. Interventional procedures 6.4.1. Botulinum toxin A (BoNTA) BoNTA has shown recent promise as a minimally invasive treatment option for IC/PBS. One prospective study recently evaluated trigonal injection of BoNTA as a treatment option for refractory IC/PBS in 26 female patients [35]. After 3 months all patients reported an improvement in their symptoms, and treatment remained effective in >50% of patients for 9 months [35]. Although the initial results with BoNTA as a reliable treatment option for refractory IC/PBS are promising, additional prospective studies will be required before its true efficacy can be clearly established. 6.4.2. Cystoscopy and hydrodistension Although hydrodistension has been used in the treatment of refractory IC/PBS for a number of years, recent data demonstrate poor long-term results with regard to symptomatic improvement. Furthermore, guidelines from the AUA recommend that highpressure, long duration hydrodistension should not be offered to patients with IC/PBS due to its inconsistent nature and increased frequency of perioperative adverse events [4]. These findings suggest that hydrodistension represents a useful diagnostic modality but remains severely limited as a reliable treatment option for IC/PBS. Diagnosis with hydrodistension includes
N.F. Davis et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 175 (2014) 30–37
36
inspection of the bladder with accurate grading of any lesions that are present:
Grade Grade Grade Grade
0: 1: 2: 3:
Normal mucosa. Petechiae in at least two quadrants. Large submucosal bleeding. Diffuse global mucosal bleeding.
6.4.3. Neuromodulation There is a paucity of available data on neuromodulation with sacral nerve stimulation and it still remains an investigational treatment option. One short-term study on 30 patients undergoing bilateral caudal epidural sacral neuromodulation for the treatment of refractory IC/PBS reported a 42% improvement in symptoms 6 months postoperatively [36]. Another more recent retrospective study demonstrated a significant improvement in suprapubic and voiding parameters in 11/21 (52%) female patients undergoing sacral nerve stimulation after 5 years of follow-up [37]. 6.4.4. Hyperbaric oxygen (HBO) HBO therapy has demonstrated significant advantages compared to a sham control for the treatment of IC/PBS after 12 months [38]. Specifically, HBO is associated with decreases in urgency and pain, but limited availability and high costs are likely to delay its progression clinically. 6.5. Surgical therapy Invasive surgical procedures are usually reserved for patients who remain refractory to conservative therapies. Pre-operatively, patients should be counselled thoroughly on the definitive nature and potential side-effects of the procedure (Table 5) 6.5.1. Transurethral resection and coagulation Hunner’s lesions can be endoscopically ablated for symptomatic relief. One early non-randomised study reported on 77 patients with Hunner’s lesions that were managed conservatively (n = 42), with fulgaration (n = 7) or with transurethral resection (n = 28). Although all patients undergoing surgical therapy experienced short-term symptomatic improvement, efficacy was not significantly superior to conservative management at 12 months [39]. Encouragingly, a more recent retrospective study evaluated the long-term outcomes of 259 transurethral resections on 103 symptomatic patients [40]. Ninety-two patients reported amelioration of their symptoms, with 40% describing symptomatic relief lasting >3 years. The authors conclude by suggesting that transurethral resection should be offered as first-line treatment for patients with classic features of IC/PBS. 6.5.2. Major surgical procedures There are three major surgical techniques for the treatment of refractory IC/PBS and each technique usually necessitates substitution of bladder tissue with a segment of bowel: (1) supratrigonal cystectomy; (2) subtrigonal cystectomy; and (3) urinary diversion radical cystectomy and urethrectomy. Supratrigonal cystectomy and enterocystoplasty represents the most favourable continence preserving technique. A number of gastrointestinal segments have been applied for trigonal augmentation, such as ileum, ileocaecum, ascending colon and sigmoid colon. Gastric tissue, however, appears less effective due to persistent production of gastric acids with resultant dysuria and suprapubic pain. Long-term results are encouraging, as described in one study on 18 patients who were followed up for 5 years [41]. Fourteen (78%) patients were completely pain free and 12 (67%) patients were able to void spontaneously. Importantly, persistent
frequency and reduced bladder capacity due to active disease in the remaining trigone and/or urethra have been reported in up to 30% of patients undergoing supratrigonal cystectomy [42]. Subtrigonal cystectomy is associated with more complications and poorer bladder rehabilitation, as the procedure typically requires ureteral reimplantation with associated risks of leakage, stricture, and reflux [43]. Indications for subtrigonal cystectomy are patients with refractory IC/PBS and biopsy proven trigonal involvement. Post-operative self-intermittent catheterisation (SIC), sexual dysfunction and voiding difficulties are more common in this patient cohort as demonstrated by Volkmer et al. in one study on eight female patients where only one patient regained normal sexual activity after undergoing subtrigonal cystectomy for IC/PBS [44]. Intuitively, urinary diversion with/without radical cystectomy is the most invasive surgical treatment option. Indications include biopsy proven involvement of the trigone (with a highly sensate urethra) and in patients unwilling or unable to perform intermittent self-catheterisation post-operatively. Simple urinary diversion with the formation of an ileal conduit is the most common surgical treatment for IC/PBS and is particularly recommended for patients with recurrent pain in the augmented bladder or continent pouch after enterocystoplasty or continent urinary diversion. 7. Conclusions Our analysis suggests that IC/PBS is under-diagnosed among the general population. Clinicians are likely to experience increasing numbers of patients with the condition as more is understood about its pathophysiology and evolving epidemiology. Therefore, urogynaecologists should sufficiently familiarise themselves with appropriate diagnostic criteria and evidence based therapies for IC/ PBS if clinical outcomes in this complex patient cohort are to improve in the near future. Financial disclosures None. Condensation Urogynaecologists should familiarise themselves with appropriate diagnostic criteria and evidence-based therapies for interstitial cystitis/painful bladder syndrome to optimise clinical outcomes in these patients. Acknowledgements None. References [1] Clemens JQ, Link CL, Eggers PW, et al. Prevalence of painful bladder symptoms and effect on quality of life in black, Hispanic and white men and women. J Urol 2007;177:1390–4. [2] Engeler DS, Baranowski AP, Dinis-Oliveira P, et al. The 2013 EAU guidelines on chronic pelvic pain: is management of chronic pelvic pain a habit, a philosophy, or a science? 10 years of development. Eur Urol 2013;64:431–9. [3] Fall M, Baranowski AP, Elneil S, et al. EAU guidelines on chronic pelvic pain. Eur Urol 2010;57:35–48. [4] Hanno PM, Burks DA, Clemens JQ, et al. AUA guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. J Urol 2011;185:2162–70. [5] Clemens JQ, Meenan RT, Rosetti MC, Gao SY, Calhoun EA. Prevalence and incidence of interstitial cystitis in a managed care population. J Urol 2005;173:98–102. discussion. [6] Park JM. Is interstitial cystitis an underdiagnosed problem in children? A diagnostic and therapeutic dilemma. Urology 2001;57(6 Suppl 1):30–1. [7] Davis NF, Breslin N, Creagh T. Using google trends to assess global interest in ‘dysport(R)’ for the treatment of overactive bladder. Urology 2013;82:1189.
N.F. Davis et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 175 (2014) 30–37 [8] Davis NF, Smyth LG, Flood HD. Detecting internet activity for erectile dysfunction using search engine query data in the Republic of Ireland. BJU Int 2012;110:E939–42. [9] Keay S, Seillier-Moiseiwitsch F, Zhang CO, Chai TC, Zhang J. Changes in human bladder epithelial cell gene expression associated with interstitial cystitis or antiproliferative factor treatment. Physiol Genomics 2003;14:107–15. [10] Vij M, Srikrishna S, Cardozo L. Interstitial cystitis: diagnosis and management. Eur J Obstet Gynecol Reprod Biol 2012;161:1–7. [11] Davis NF, McGuire BB, Callanan A, Flood HD, McGloughlin TM. Xenogenic extracellular matrices as potential biomaterials for interposition grafting in urological surgery. J Urol 2010;184:2246–53. [12] Parsons CL. The role of the urinary epithelium in the pathogenesis of interstitial cystitis/prostatitis/urethritis. Urology 2007;69(4 Suppl):9–16. [13] Lokeshwar VB, Selzer MG, Cerwinka WH, et al. Urinary uronate and sulfated glycosaminoglycan levels: markers for interstitial cystitis severity. J Urol 2005;174:344–9. [14] Smith SD, Wheeler MA, Foster Jr HE, Weiss RM. Urinary nitric oxide synthase activity and cyclic GMP levels are decreased with interstitial cystitis and increased with urinary tract infections. J Urol 1996;155:1432–5. [15] Silk MR. Bladder antibodies in interstitial cystitis. J Urol 1970;103:307–9. [16] Warren JW, Jackson TL, Langenberg P, Meyers DJ, Xu J. Prevalence of interstitial cystitis in first-degree relatives of patients with interstitial cystitis. Urology 2004;63:17–21. [17] Lubeck DP, Whitmore K, Sant GR, Alvarez-Horine S, Lai C. Psychometric validation of the O’leary–Sant interstitial cystitis symptom index in a clinical trial of pentosan polysulfate sodium. Urology 2001;57(6 Suppl 1):62–6. [18] van de Merwe JP, Nordling J, Bouchelouche P, et al. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal. Eur Urol 2008;53:60–7. [19] Mulholland SG, Hanno P, Parsons CL, Sant GR, Staskin DR. Pentosan polysulfate sodium for therapy of interstitial cystitis. A double-blind placebo-controlled clinical study. Urology 1990;35:552–8. [20] Nickel JC, Barkin J, Forrest J, et al. Randomized, double-blind, dose-ranging study of pentosan polysulfate sodium for interstitial cystitis. Urology 2005;65:654–8. [21] van Ophoven A, Pokupic S, Heinecke A, Hertle L. A prospective, randomized, placebo controlled, double-blind study of amitriptyline for the treatment of interstitial cystitis. J Urol 2004;172:533–6. [22] Sairanen J, Tammela TL, Leppilahti M, et al. Cyclosporine A and pentosan polysulfate sodium for the treatment of interstitial cystitis: a randomized comparative study. J Urol 2005;174:2235–8. [23] Sant GR, Propert KJ, Hanno PM, et al. A pilot clinical trial of oral pentosan polysulfate and oral hydroxyzine in patients with interstitial cystitis. J Urol 2003;170:810–5. [24] Thilagarajah R, Witherow RO, Walker MM. Oral cimetidine gives effective symptom relief in painful bladder disease: a prospective, randomized, doubleblind placebo-controlled trial. BJU Int 2001;87:207–12. [25] Sant GR, LaRock DR. Standard intravesical therapies for interstitial cystitis. Urol Clin North Am 1994;21:73–83. [26] Perez-Marrero R, Emerson LE, Feltis JT. A controlled study of dimethyl sulfoxide in interstitial cystitis. J Urol 1988;140:36–9. [27] Steinhoff G, Ittah B, Rowan S. The efficacy of chondroitin sulfate 0.2% in treating interstitial cystitis. Can J Urol 2002;9:1454–8.
37
[28] Nickel JC, Egerdie RB, Steinhoff G, Palmer B, Hanno P. A multicenter, randomized, double-blind, parallel group pilot evaluation of the efficacy and safety of intravesical sodium chondroitin sulfate versus vehicle control in patients with interstitial cystitis/painful bladder syndrome. Urology 2010;76:804–9. [29] Peeker R, Haghsheno MA, Holmang S, Fall M. Intravesical bacillus Calmette– Guerin and dimethyl sulfoxide for treatment of classic and nonulcer interstitial cystitis: a prospective, randomized double-blind study. J Urol 2000;164:1912–5. discussion 5–6. [30] Riedl CR, Engelhardt PF, Daha KL, Morakis N, Pfluger H. Hyaluronan treatment of interstitial cystitis/painful bladder syndrome. Int Urogynecol J Pelvic Floor Dysfunct 2008;19:717–21. [31] Morales A, Emerson L, Nickel JC. Intravesical hyaluronic acid in the treatment of refractory interstitial cystitis. Urology 1997;49(5A Suppl):111–3. [32] Ahmad I. Sarath Krishna N, Meddings RN. Sequential hydrodistension and intravesical instillation of hyaluronic acid under general anaesthesia for treatment of refractory interstitial cystitis: a pilot study. Int Urogynecol J Pelvic Floor Dysfunct 2008;19:543–6. [33] Apostolidis A, Gonzales GE, Fowler CJ. Effect of intravesical Resiniferatoxin (RTX) on lower urinary tract symptoms, urodynamic parameters, and quality of life of patients with urodynamic increased bladder sensation. Eur Urol 2006;50:1299–305. [34] Payne CK, Mosbaugh PG, Forrest JB, et al. Intravesical resiniferatoxin for the treatment of interstitial cystitis: a randomized, double-blind, placebo controlled trial. J Urol 2005;173:1590–4. [35] Pinto R, Lopes T, Frias B, et al. Trigonal injection of botulinum toxin A in patients with refractory bladder pain syndrome/interstitial cystitis. Eur Urol 2010;58:360–5. [36] Zabihi N, Mourtzinos A, Maher MG, Raz S, Rodriguez LV. Short-term results of bilateral S2–S4 sacral neuromodulation for the treatment of refractory interstitial cystitis, painful bladder syndrome, and chronic pelvic pain. Int Urogynecol J Pelvic Floor Dysfunct 2008;19:553–7. [37] Ghazwani YQ, Elkelini MS, Hassouna MM. Efficacy of sacral neuromodulation in treatment of bladder pain syndrome: long-term follow-up. Neurourol Urodyn 2011;30:1271–5. [38] van Ophoven A, Rossbach G, Pajonk F, Hertle L. Safety and efficacy of hyperbaric oxygen therapy for the treatment of interstitial cystitis: a randomized, sham controlled, double-blind trial. J Urol 2006;176:1442–6. [39] Greenberg E, Barnes R, Stewart S, Furnish T. Transurethral resection of Hunner’s ulcer. J Urol 1974;111:764–6. [40] Peeker R, Aldenborg F, Fall M. Complete transurethral resection of ulcers in classic interstitial cystitis. Int Urogynecol J Pelvic Floor Dysfunct 2000;11:290–5. [41] van Ophoven A, Oberpenning F, Hertle L. Long-term results of trigone-preserving orthotopic substitution enterocystoplasty for interstitial cystitis. J Urol 2002;167:603–7. [42] Blaivas JG, Weiss JP, Desai P, Flisser AJ, Stember DS, Stahl PJ. Long-term followup of augmentation enterocystoplasty and continent diversion in patients with benign disease. J Urol 2005;173:1631–4. [43] Fall M, Oberpenning F, Peeker R. Treatment of bladder pain syndrome/interstitial cystitis 2008: can we make evidence-based decisions. Eur Urol 2008;54:65–75. [44] Volkmer BG, Gschwend JE, Herkommer K, Simon J, Kufer R, Hautmann RE. Cystectomy and orthotopic ileal neobladder: the impact on female sexuality. J Urol 2004;172:2353–7.
