Disruption of the mucin GAG layer of the bladder urothelium has been implicated in the pathogenesis of IC/BPS. The main components of the GAG layer include chondroitin sulfate, hyaluronic acid (HA), heparin sulfate, dermatan sulfate, and keratin sulfate [11]. Therapeutic GAG or GAG-like agents, such as HA, chondroitin sulfate, heparin, and pentosanpolysulfate have been previously used with variable and somewhat disapponting results [12–14].

Pentosan polysulfate sodium (PPS), a synthetic sulphated polysaccharide, is the most frequently GAG-like agent used to replace defective GAGs. Since the preliminary study of Parsons and co-workers in 1983 [15], this agent has been used orally or intravesically administered, in a number of studies. PPS is the only oral medication for IC/BPS approved by the US Food and Drug Administration. The study with the longest follow-up with oral PPS remains that of Hanno and co-workers [16]. In this study, oral PPS 100 mg three times daily induced about a 50% positive response in pain and urgency in IC/BPS patients. PPS has been used alone or in combination with different pharmacological agents [17–20]. In randomized controlled studies, with different doses of oral PPS for different times, the drug has been compared with placebo, heparin, hydroxyzine, cyclosporine A, intravesical liposomes, intravesical PPS, bladder hydrodistension [14, 21–25].

One double-blind, placebo-controlled trial reported subjective improvement in pain, urgency and frequency in patients taking PPS compared to the control group [23]. Longer durations of treatment associated with greater response rates with 50% of patients reporting an improvement after 26 week course. Overall, few of these studies were of high quality, as reported in recent systematic reviews with meta-analysis, with 1b level of evidence and grade of recommendations C [4–6]. According to AUA guidelines, PPS may be administered as second line oral medication [3].

Chondroitin sulfate and Hyaluronic acid. Many uncontrolled single-center studies including a small number of patients have been performed with the use of these agents in the treatment of IC/BPS, suggesting that both intravesical chondroitin sulfate and hyaluronic acid can improve symptoms in IC/PBS patients [26–29]. Indeed, in IC/BPS the concentration of these substances in the urothelium is reduced and urothelial permeability toward potassium compounds is increased, causing bladder pain. The potential benefit of chondroitin sulfate was detected by Nickel and co-workers in a randomized controlled study [30]. Although the study was not powered to show a significant difference between active therapy and vehicle control, many patients reported a clinically significant benefit with intravesical chondroitin sulfate treatment as compared with placebo. Intravesical chondroitin sulphate has been observed to induce side effects as dysuria, nausea, gastrointestinal upset, macular rash and urethritis in 77% of patients [26–30]. Also chondroitin sulfate and hyaluronic acid have been used alone or in combination with other pharmacological agents (i.e. heparin, lidocaine) and with bladder hydrodistension [4–6]. A positive and durable impact of HA therapy on IC/PBS symptoms was observed by Riedl and co-workers, with 85% patients reporting symptom improvement (> or =2 VAS units) [31]. HA with bladder hydrodistension, together with the addition of KCl and NaCl induced a 62.5% and 71.48% improvements on pain in the study of Daha and co-workers [32]. In the study of Shao et al. [33], HA alone or in combination with hydrodistention, lidocaine and heparin did not induce any improvement in pain, bladder capacity or urinary frequency.

Overall, the use of these GAG-like agents require additional clinical randomised controlled studies in order to better define which is their effect in the treatment of IC/BPS patients.

The role of antihistamines in controlling symptoms of IC/BPS is still controversial. The histamine receptor antagonist hydroxyzine blocks the H1-receptor subtypes and inhibits the activation of mast cells. Previous studies reported an improvement in >90% of IC/BPS patients treated with this medication [4–6]. However, a more recent prospective, randomised controlled trial did not demonstrate any statistically significant improvement with hydroxyzine compared to a placebo [22].

The H2- receptor antagonist cimetidine has been observed to be effective in controlling IC/BPS symptoms in 71% of treated patients, with a dosage of 200 mg three times daily. A subsequent, 3- month follow up randomised controlled trial confirmed these previous results [34].

To date there is enough evidence that amitriptyline increasing doses (from 25 to 100 mg) administered for some months is able to control pain and urgency in IC/BPS patients, as demonstrated by the study of van Opoven et al. [35]. In another high quality study, amitriptyline with different dosages and times of administration (increasing doses once daily from 10 to 75 mg for 12 weeks) with the addition of behavioural modification, showed a great effect size in ICSI and urinary frequency [36]. Importantly, amitriptyline is associated with high rates of significant side-effects, as dry mouth, dizziness and gastrointestinal problems, which limit the long term use of the substance. Nevertheless, both AUA and EAU recommended amitriptyline as a treatment option for IC/PBS patients [2, 3]. Other anti-depressant drugs potentially useful for the treatment of IC/BPS patients could be doxepin, desipramine and duloxetine [37], but the available data on their efficacy are still very limited.

Cyclosporine A (CYA). CyA is a potent immunosuppressive agent used to decrease the risk of rejection after organ transplantation and to treat autoimmune conditions such as psoriasis, atopic dermatitis and rheumatoid arthritis [38]. It has been hypothesized that CyA binds to cyclophilins in T cells to antagonize the calcineurin mediated dephosphorylation of inactive nuclear factor of activated T cells, which is required for T cell activation [38]. One study compared CyA 1.5 mg/kg twice daily versus low dose PPS for 6 months in patients affected by IC/BPS [24]. A significantly higher response rate was detected with CyA (75% vs. 19%, P < 0.05), particularly on three outcomes (pain, frequency and IC Symptom Index). Mild adverse events were common in the CyA arm, and were reported by a total of 30 patients (among 32) compared to 18 (among 32) patients in the PPS arm. Significant adverse events (increased blood pressure and serum creatinine) were reported in the CyA arm. At 6 months patients were asked if they wanted to proceed with the current treatment. A total of 19 patients chose to continue on CyA treatment and 4 patients continued on PPS treatment.

Other potential immunosuppressive agents for IC/PBS could be methotrexate and suplatast tosilate [39, 40] but data on their therapeutic potential are to date really limited. With regards to the use of corticosteroids in patients with IC/BPS, AUA guidelines recommend that oral long-term glucocorticoid therapy should not be offered as treatment in patients with IC/BPS [3].

It has been shown that nerve growth factor (NGF) is involved in inflammation, and allergic reaction, and altered neurological conditions in IC/BPS [41]. An immunohistological study reports that expression of NGF is increased in the bladder of IC/BPS patients [42]. Neurotrophic factors including NGF are also found in urine obtained from IC/BPS patients [43] and a recent meta-analysis study reported that urinary NGF could be a useful biomarker for the differential diagnosis of IC/BPS and overactive bladder as well as a predictive biomarker to help guide treatments [44]. Evans et al. [45] reported the clinical outcome of tanezumab, a monoclonal NGF neutralizing antibody for IC/BPS in phase II study. Tanezumab was administered intravenously in 68 patients with IC/BPS, and effective for self-reported pain and urinary urgency for 6 weeks compared to the placebo group, while voiding frequency and voided volume are not affected. However, serious adverse events were reported by another clinical trial of tanezumab for osteoarthritis, in which bone necrosis developed and total joint replacements were needed, and several clinical trials have since been terminated (www.​clinicaltrials.​gov). However, another human monoclonal antibody directed against NGF, fulranumab, did not show efficacy, but the authors did not exclude the possibility that the drug would provide clinical benefit in a larger study and/or specific populations [46]. Thus, these results provide the proof-of-concept evidence showing that NGF is an important pathophysiological factor inducing pain-related symptom in IC/BPS and that intervention of the NGF mechanism is effective for the treatment of IC/BPS; however, another local approach such as liposome-based intravesical therapy targeting NGF [47] should be developed to avoid systemic adverse events in future.

Local anesthetics such as lidocaine, which suppress neuronal excitation, have demonstrated properties that block the neuroinflammatory cycle associated with IC/BPS [48]. Intravesical lidocaine has been shown to be an effective treatment for IC/BPS. A clinical trial reported that alkalinized lidocaine and sodium bicarbonate relieve IC/BPS symptoms, as reported in the significant decrease of the GRA score, compared to the placebo (30% and 9.6%, respectively) [49]. The success rate is relatively higher than other intravesical drugs, but the post-therapeutic observation period is short; therefore, the treatment is also defined as an option in the AUA guideline [3].

The lidocaine-releasing intravesical system (LiRIS^®) is a solid mini pellet, which encases lidocaine in a water-permeable flexible tube and releases lidocaine continuously [50]. In this open-label clinical trial without a placebo arm in 16 IC/BPS women with bladder pathologies such as Hunner lesions or glomerulations identified cystoscopically, clinically meaningful reductions in pain, urgency, voiding frequency, and disease questionnaires were seen after 14 days of LiRIS treatment. Cystoscopic examinations showed improvement on day 14 (day of removal) compared with day 1, including resolution of Hunner lesions in five of six subjects with baseline lesions. Extended follow-up suggests that the reduction in pain was maintained for several months after the device was removed [50].

These results of intravesical lidocaine treatment in IC/BPS patients suggest that; (1) lidocaine can reduce not only symptoms, but also neurogenic inflammation in the bladder by blocking nerve activity, (2) the bladder is a triggering organ of pain symptoms in the significant number of IC/BPS patients, especially when the bladder pathology is identified and (3) intravesical lidocaine administration would be useful as a diagnostic test to identify the patient population that is suitable for bladder-targeting therapies.

Bladder distention releases ATP from the urothelium, and ATP activates P2X3 receptors in bladder afferents to modulate bladder activity evidenced by experimental studies of P2X3 knockout mice [51]. There is also evidence showing that the stimulatory ATP mechanism is upregulated in the bladder from IC/BPS patients because ATP release from urothelial cells in addition to urothelial expression of P2X3 ATP receptors are increased in IC/BPS patients [52–55]. A recent placebo-controlled clinical trial in 36 women treated with AF-219 and 38 women treated with placebo showed that patients treated with AF-219 for 4 weeks [56] had improvement in the key symptoms of IC/BPS such as pain scores, urinary urgency and in Global Response Assessment (GRA), compared to placebo-treated patients. There were 5 patients (4 in the AF-219 arm and 1 in the placebo arm) with Hunner lesions on cystoscopy. Thus, targeting the ATP and P2X receptor mechanism in the bladder would be a promising strategy for the treatment of IC/BPS with or without Hunner lesions.

A new pharmaceutical class of compounds, represented by AQX-1125, has been recently introduced. AQX-1125 activates SH2-containing inositol-5′-phosphatase (SHIP1), modulating the PI3K pathway [57], which is involved in processes like cell growth, activation and immune/inflammatory conditions. Activation of SHIP1 has an anti-inflammatory effect by negatively regulating the PI3K pathway to reduce the immunological reaction [57]. AQX-1125 has been studied in a short-term, phase II, randomized, placebo controlled study, which included patients with moderate to severe IC/BPS, some with Hunner lesions (Aquinox Trial) [58]. Thirty-seven IC/BPS women were treated with the compound and 32 with placebo. Women treated with AQX-1125 showed a significant reduction in bladder pain and improvement of symptoms at 6 weeks compared to placebo-treated women [58].