Pharmacokinetic considerations for therapies used to treat interstitial cystitis.

Review

Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by University of Toronto on 12/22/14 For personal use only.

Pharmacokinetic considerations for therapies used to treat interstitial cystitis 1.

Introduction

2.

Dysfunctional bladder urothelium

3.

Mast cell activation

4.

Neural sensitization

5.

Expert opinion

Barbara Gardella, Daniele Porru, Massimo Allegri, Stefano Bogliolo†, Anna Daniela Iacobone, Cristina Minella, Rossella Elena Nappi, Simone Ferrero & Arsenio Spinillo †

IRCCS-Fondazione Policlinico San Matteo and University of Pavia, Department of Obstetrics and Gynaecology, Pavia, Italy

Introduction: Interstitial cystitis (IC) or bladder pain syndrome (BPS) is defined as supra-pubic pain related to bladder filling. IC is characterized by a particular symptom complex with no identifiable causes; as with bladder hypersensitivity it is usually associated with urinary frequency and urgency with bladder pain. No current treatments have a significant impact on symptoms over time. Areas covered: This systematic review examines the pharmacokinetic aspects and adverse event of present IC therapy to highlight appropriate treatment to improve the symptoms of IC. This article reviews material obtained via Medline, PubMed, and EMBASE literature searches up to October 2013. Expert opinion: The correct approach to IC should consider a multidisciplinary team of specialists and a multimodal treatment package that include psychotherapy, behavior change, physical activation, and analgesic treatment. Unfortunately, a single therapeutic target for IC is not yet known. With regard to pathophysiology and therapy, there is more to discover. The first insult damages the bladder urothelium, hence vehicles that lead the drug to penetrate the wall of the bladder might be a novel strategic approach. Keywords: biofilms, bladder pain syndrome, interstitial cystitis, intravesical liposomes Expert Opin. Drug Metab. Toxicol. (2014) 10(5):673-684

1.

Introduction

Interstitial cystitis (IC) or bladder painful syndrome (BPS) is defined as supra-pubic pain related to bladder filling, in association with other urological symptoms, such as increased day- and night-time urinary frequency and urgency in the absence of proven urinary tract infection or obvious organic urological disease [1]. Current thought implicates an initial unidentified insult to the bladder, triggering inflammatory, followed by neuroplasticity and neural sensitization [2]. This may happen in patients with an underlying systemic defect. Several opinion leaders hypothesized that IC/BPS is not an isolated clinical entity, but rather a symptom of complex regional pain syndrome (CRPS). In fact, patients suffering from IC/BPS are more likely to have other CRPS such as vulvodynia or irritable bowel syndrome [3], thus leading to a more difficult management of chronic pain. The multiple theories of pathogenesis proposed for IC/BPS provoked the development of multiple treatments, without any evidence of decisive efficacy for anyone of these yet. This systematic review examines the pharmacokinetic (PK) and adverse events of IC/BPS therapy. The following electronic databases were used for literature research: Medline, PubMed, and EMBASE from inception until December 2013. 10.1517/17425255.2014.896338 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted

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At current knowledge, there is no evidence of decisive efficacy for anyone of the multiple therapies developed for interstitial cystitis/bladder pain syndrome (IC/BPS). A correct approach should consider a multimodal treatment package. The treatment of IC/BPS includes the option of intravesical delivery of drugs, such as local anesthetics, hyaluronic acid, and chondroitin sulfate, aiming to repair the urothelial glycosaminoglycans (GAGs) layer. Vehicles that improve bladder uptake of instilled substances might be a novel strategic approach. Pentosan polysulfate (PPS) is the only oral medication approved for use in patients with IC/BPS. PPS acts to repair GAGs layer and it may have anti-inflammatory effects by inhibition of mast cell degranulation. Hydroxyzine and other immunomodulatory therapies have been reported to be useful for the symptomatic treatment of IC/BPS, as it might be considered as one of the allergic disorders of the urogenital system. Antidepressants and anticonvulsants can be effective against chronic pain by directly suppressing the nervous mechanisms underlying pain and/or by alleviating depression symptoms caused by the ability to experience pain. Analgesics, such as NSAIDs and opioids, could be really helpful in order to potentiate descendent inhibitory pathways. Nevertheless, there are no studies that actually prove the efficacy of these drugs in the treatment of IC/BPS.

This box summarizes key points contained in the article.

The following search terms were used: ‘interstitial cystitis, chronic pelvic pain syndrome, pathophysiology, treatment, and pharmacokinetics’. All pertinent manuscripts were carefully evaluated and their reference lists were examined in order to find other articles that could be included in this review. 2.

Dysfunctional bladder urothelium

Bladder urothelium has both an ‘afferent’ function and an ‘efferent’ (or paracrine) function [4,5]: in fact, information on local stimuli reaches the CNS, and this is involved in the control of micturition reflex and pain reflex; besides, the release of mediators (such as substance P and tachykinins) causes smooth muscle contraction and local inflammation. In various chronic inflammatory bladder diseases, such as recurrent urinary tract infections, chemical or radiation cystitis, and IC/BPS, the early stages of the inflammatory process display the loss of the glycosaminoglycans (GAGs) mucous layer independently of the original cause [6]. As a consequence of inflammation of subepithelial layers, peptide-containing fibers of suburothelium activate and cause hypersensitivity with allodynia, frequency, urgency, and pain with bladder filling. The treatment of chronic cystitis includes the option of intravesical therapy with substances aiming to repair the urothelial GAGs layer. Recent data show an association 674

between suburothelial inflammation, increased urothelial cell apoptosis, decreased junction protein expression and clinical symptoms in IC/BPS [7]. Intravesical drug delivery Intravesical drug delivery (IDD) consists in the administration of a drug or a combination of drugs directly into the bladder; it is an efficient alternative to systemic drug delivery (Table 1). Systemic side effects are thus reduced and the effect of the substance introduced into the bladder improves the exposure of the affected bladder lining to the therapeutic agent. The urinary bladder is relatively accessible by catheters, as compared to other organs. IDD allows localized treatment and allows a better contact of the drug with the diseased tissues. IDD has its inherent limitations as well. The periodical voiding of urine from the bladder washes out drug solutions instilled in the bladder, thus requiring frequent dosage and greatly reducing the residence time of the drug in the bladder. Furthermore, the urothelium has very low permeability, which represents a limit to the efficacy of IDD. Even if abnormal, the urothelial layer does not allow penetration of the drug into the bladder wall; therefore, different permeation enhancers are needed to increase transfer of the therapeutic agent into the abnormal tissues. 2.1

Local anesthetics Local anesthetics are increasingly recognized as having powerful broad-spectrum anti-inflammatory effects, including stabilizing mast cells and blocking histamine release. Theoretically, they appear to be ideally suited to suppress the neuroinflammatory cycle occurring in IC/BPS. However, ion trapping in the bladder results in poor absorption of local anesthetics, with peak serum lidocaine levels reaching 0.1 µg/ml [8]. Nickel et al. assessed the relief of the symptoms of IC/BPS after a consecutive 5-day course of treatment with intravesical alkalinized lidocaine (PSD597, AIL), characterizing the PKs of single and multiple doses of intravesical PSD597 in a subgroup of patients [9]. A significant number of patients treated with PSD597 had a moderate or marked improvement of the Global Response Assessment scale after completing the 5-day course of treatment. The response rate was 30% with active treatment and 9.6% with placebo (p = 0.012). The peak serum lidocaine concentration during the study was < 2 µg/ml, and well below the toxic level (> 5 µg/ml). This preliminary study showed that PSD597 was partially effective for providing sustained amelioration of symptoms of IC/BPS beyond the acute treatment phase. The drug was safe, well tolerated, and devoid of systemic side effects. In a study performed by Henry et al. [8], healthy volunteers and IC patients had similar lidocaine absorption profiles with peak levels occurring at about 30 min. The mean peak was 1.06 µg/ml (range of 0.66 -- 1.71 µg/ml) for the healthy volunteers group and 1.6 µg/ml (range of 0.2 -- 2.0 µg/ml) for IC patients. The mean pain scores in the IC group decreased from a baseline of 6.0 -- 1.8 on day 1 -- 0.6 on 2.2

Expert Opin. Drug Metab. Toxicol. (2014) 10(5)

Pharmacokinetic considerations for therapies used to treat interstitial cystitis

Table 1. Summary of current intravesical agents in interstitial cystitis/bladder pain syndrome.


Intravesical agent Dimethyl sulfoxide Heparin Hyaluronic acid Chondroitin sulfate Pentosan polysulfate Capsaicin/resiniferatoxin Bacillus Calmette-Gue´rin Oxybutinin Lidocaine Botulinum toxin Neuromodulation Liposomes

Current status FDA approved Clinical testing Clinical testing Clinical testing Case reports Clinical testing Abandoned Clinical testing Clinical testing Clinical testing Clinical testing Clinical testing

in progress in progress in progress in progress in in in in in

progress progress progress progress progress

Reprinted with permission of MedReviews, LLC [14]. All rights reserved. MedReviews, LLC.

day 2. In both groups a temporary urethral discomfort after voiding the buffered lidocaine was perceived. AIL improves lidocaine absorption from the bladder, as indicated by therapeutic systemic lidocaine levels in both healthy and IC patients. Furthermore, the decrease in acute pain scores in the IC group indicated sufficient concentration of local anesthetic within the bladder wall to block the sensory neurons within the submucosal plexus. AIL is one of the few agents with data on PK studies for the treatment of IC and warrants further investigation. Approaches used to improve bladder uptake of instilled drugs

2.3

Various approaches have been attempted to improve bladder uptake of instilled drugs (Figure 1). In addition, most small molecule drugs can perform better after instillation if their PK half-life is extended. In fact, unlike neurotoxins such as botulinum toxin, that are gifted with long-lasting duration of action because of their irreversible cleavage of target protein, small molecules have limited half-life and longer adhesion and exposure time would be a major benefit. It was demonstrated that increased bladder residence time translates into improvement in activity [10]. Physical methods such as the use of electromotive force [11] to accelerate passive diffusion has been clinically accepted, while enhancement of penetration using chemical methods (such as dimethyl sulfoxide [DMSO], chitosan, and other biomolecules) has yet to be optimized for large-scale use. Chemical penetration enhancers can be used to chemically interact with components of bladder urothelium, thereby enhancing penetration of drug formulations into the bladder wall. One such agent used to treat IC is DMSO, a solvent with antibacterial and anti-inflammatory properties. DMSO can penetrate tissues without damaging them. It has been used to enhance transport of chemotherapeutic drugs such

as cisplatin, doxorubicin and pirarubicin into bladder cancer [12]. Chitosan is one of the polysaccharides widely used for permeability enhancement of drug solutions through the urothelium. It is formed by cross-linking glucosamine and N-acetylglucosamine units by bifunctional glutaraldehyde [13]. Chitosan derivatives have also been used for treatment of IC; the sulfated form of chitosan (N-sulfonato-N,O-carboxymethylchitosan, sNOCC) was used to encapsulate and transport the anti-inflammatory agent (5-aminosalicylic acid) into the bladder wall in rat models using protamine-sulfate-induced cystitis [14]. Advances in the development of bladder coating with liposomes are expected to further improve the efficacy and safety of pharmacotherapy for bladder diseases in the future [15]. Liposomes have been used to enhance delivery of the neurotoxin capsaicin for the treatment of IC. Liposomes not only provide a biocompatible interface with affinity for bladder surface but they can also facilitate absorption of high molecular weight drug and biologic agent by vesicular traffic. The latest developments in the field of nanotechnology can bring this mode of therapy as a new hope to the forefront of disease management for the lower urinary tract [15]. One of the major improvements in IDD options is the use of mucoadhesive biomaterials as drug carriers. These can adhere efficiently to the mucous membrane of the urothelium, enabling the carriers to stay attached to the bladder wall even during urine voiding. This greatly increases the residence time of the drug in the bladder and allows sustained drug delivery over a prolonged time span, thereby eliminating the need for repeated drug infusions. Hydrogels, such as the thermo-responsive polymeric PEG--PLGA--PEG system, can be modified to allow injection of the polymer suspension in a liquid state into the bladder, which then forms an in situ polymeric gel layer that stays strongly adhered to the bladder wall. Many such polymers have shown such properties but have yet to be utilized for intravesical applications [15]. Hyaluronic acid and chondroitin sulfate Recent preliminary studies [16,17] looked at intravesical instillations of hyaluronic acid plus chondroitin sulfate based on the hypothesis that they may lead to regeneration of the damaged GAG layer in IC/BPS. Unfortunately, there are no available data regarding PKs of these drugs yet. Nevertheless, the encouraging outcomes in terms of pain relief and reduction of frequency push to better analyze this combination of medications for intravesical instillation. 2.4

Pentosan polysulfate Pentosan polysulfate (PPS) is the most studied oral medication in use for IC/BPS and is the drug only approved by the US FDA for use in patients with IC [18]. PPS is a semi-synthetic, sulfated polysaccharide, which is chemically and structurally similar to heparin and GAG. Its precise mechanism of action has not been defined, but PPS 2.5


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Bioadhesive microspheres for drug delivery

Liposomes for drug and gene siRNA delivery Thermosensitive hydrogel

Iontophoresis $ electroporation for drug delivery

Cell penetrating peptides (amphipathic helix)

Virus for gene delivery

Figure 1. Advanced delivery options for intravesical drug or gene delivery. Anatomic location of bladder allows development of various drug delivery platforms such as virus, liposomes, microspheres, polymeric hydrogel, and cell penetrating peptides. Reprinted with permission of MedReviews, LLC [14]. All rights reserved. MedReviews, LLC.

is believed to restore the normal protective barrier between bladder and urine. Preliminary clinic models suggest that PPS acts to repair GAG layer that lines the bladder and controls the permeability of urothelium [19]. In addition, in vitro studies suggest that it may have anti-inflammatory effects by inhibition of mast cell degranulation [20]. In literature there are several data on the use of PPS for IC/ BPS, even if these are very different from each other as regards the dosage and the duration of treatment [21,22]. Indeed the bioavailability of PPS is very low (< 3%). The maximum plasma concentration of PPS occurs within 2 h of oral administration. Liver and spleen are the sites of desulfation and kidneys are the sites of depolymerization of PPS, although a large amount of unchanged drug is excreted in the feces (~ 52%) and a small amount in the urine [23]. For all these reasons, it should be more advisable a multiple-dose administration rather than a single-dose. Unfortunately, although five 676

randomized clinical trials about the use of PPS are available, a meta-analysis of all these studies showed differences (95% confidence limits) in pain (16.6%, NNT = 7), in urgency (13%, NNT = 7.5) and in frequency (16.7%, NNT = 6). These results are statistically significant but not clinically relevant [24]. In his review, Nickel describes the biggest limitations of the major study regarding the use of PPS, in particular the absence of a placebo testing, but also highlights how important knowledge derives from post hoc analysis [25]. Oral PPS owns a really good clinical efficacy if started very early, when symptoms are already present but a diagnosis of IC/ BPS has not been formulated yet, since its goal is to repair the dysfunctional bladder urothelium [26]. The efficacy is not dose-dependent, but it is advisable a three-dose administration because of the PPS PK profile. Furthermore, when a clinical efficacy is assessed in the first 6 months of treatment, this could increase up to reach a percentage of success of 67% after



32 weeks [27]. On the contrary, it is recommended to shift to a multidrug therapy in patients with an intermediate reaction to PPS. In fact, there is no evidence for a treatment longer than 6 months if no proven advantage has been shown. 3.

Mast cell activation

Hydroxyzine Hydroxyzine is a heterocyclic piperazine histamine-1 receptor antagonist, which has been reported to be useful for the symptomatic treatment of IC, especially in patients suffering from allergies [28]. The effectiveness of hydroxyzine is not due to its anti-histaminic properties, since other common H1-receptor antagonists are ineffective in the treatment of IC. It can substantially inhibit connective tissue mast cell secretion by neurogenic stimuli along with its anticholinergic, anxiolytic, and analgesic properties. In fact, a role of bladder mast cell activation has been documented in IC [29,30]. It reaches a peak serum concentration in about 2 h after oral administration and is almost entirely metabolized and cleared through kidneys and liver. Furthermore, the use of hydroxyzine at bedtime is not only indicated by its long half-life (3 -- 20 h in adults), but also by the possibility of reducing its adverse events, while maintaining its beneficial effects during the day [31,32]. Sant et al. performed a pilot clinical trial to evaluate the efficacy of oral PPS and hydroxyzine in reducing pain, urgency, and frequency. The response rate for hydroxyzine was 31% for patients treated and 20% for non-treated patients (p = 0.26), while a nonsignificant trend was reported in the PPS treatment group (34%) compared to no PPS (18%, p = 0.064) [33].


3.1

Immunomodulatory therapies Given the evidence that over 50% of patients suffer from allergies, IC might be considered as one of the IgE mediated, mast-cell-driven allergic disorders of the urogenital system. In fact, IC has been related to some histopathologic abnormalities similar to those observed in allergic disorders, including mast cell activation, histamine release, and eosinophil infiltration. In line with this, Lee et al. reported a case of IC successfully controlled primarily by omalizumab, a chimeric monoclonal anti-immunoglobulin E antibody that eliminates serum IgE, preventing attachment onto mast cells and subsequent histamine release from mast cells. The improvement was also maintained by specific immunotherapy [34]. According to this postulated pathophysiology, some IC/BPS patients can be well managed even with immunosuppressive treatment, such as a combination therapy of prednisolone and tacrolimus [35]. IC has also been associated with inappropriate leukotriene release, which is the target of montelukast therapy, through inhibition of the leukotriene D4 (LTD4) receptor [36]. Upon mast cell activation, LTC4 is synthesized and released from mast cells and subsequently converted to biologically 3.2

active LTD4 in the bladder wall, where, after binding to its receptor, it is responsible for the symptoms observed in IC patients [37]. Montelukast is an orally active compound that acts as leukotriene receptor antagonist and is commonly used in the treatment and prevention of allergic rhinitis and asthma. In the bladder wall, montelukast antagonizes LTD4 receptors, which are responsible for the spasmogenic effects on the detrusor muscle of the bladder in IC. A small study of women with IC reported a significant decrease in urinary symptoms (24-h urinary frequency, nighttime voiding, pain, etc.) after only 1 month of treatment with montelukast [38]. 4.

Neural sensitization

Antidepressants and anticonvulsants have extensively been used in treatment of chronic pain conditions such as CRPS [39], also because this type of pain can be treated with these drugs in doses below those at which they act as antidepressants and anticonvulsants. Tricyclic antidepressant Among antidepressants, amitriptyline is a tricyclic antidepressant (TCA) of considerable importance, because this drug is widely used to treat chronic neuropathic pain. Amitriptyline is recognized as useful therapy for IC or BPS, for at least three major pharmacological mechanisms. It is an effective TCA that inhibits the reuptake of serotonin and noradrenalin at pre-synaptic nerve ends and the anticholinergic reaction of the CNS and peripheral nerves, which in turn leads to sedation due to an antihistamine reaction in the CNS [40]. TCAs are used to treat various pain syndromes and cause effects such as increased pain tolerance through activation of noradrenergic inhibitory pathways. They can be effective against chronic pain by directly suppressing the nervous mechanisms underlying pain and/or by alleviating depression symptoms caused by the ability to accept pain or experience pain. TCAs control the activation and suppression of peripheral neurons or modulate the neuronal inhibitory or stimulatory pathways in the spine or supraspinal segments. Such mechanisms alleviate pain symptoms by suppressing acetylcholine, histamine, and the H1 receptor and by inhibiting the reuptake of released serotonin and norepinephrine [41]. Recent studies showed a strong relation between immune, endocrine, and nervous systems in the maintenance of chronic pain, where serotonin 5-hydroxytryptamine (5-HT) plays significant role [42]. It is already known that 5-HT inhibits the generation of painful stimuli on the CNS level, but recent evidence indicates that 5-HT might be associated also with an increase pain transmission from the periphery, where mast cells play an important role. In fact, TCAs could also influence mast cell-derived 5-HT levels, via at least three different mechanisms: secretion of 5-HT, uptake of exogenous 5-HT, and reuptake of secreted 5-HT [42]. 4.1


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Amitriptyline is rapidly and completely absorbed from the gastrointestinal tract with peak plasma concentrations occurring between 2 and 12 h after administration, but individual response can vary considerably. Bioavailability of the drug ranges between 30 and 60%, due to extensive first-pass metabolism in the liver, where it is demethylated to its primary active lipophilic metabolite, nortriptyline, which may reach high concentration in plasma comparable to the parent drug, and crosses the blood--brain barrier. Volume of distribution is found to be 11 -- 18 l/kg and plasma protein binding is > 90%, predominantly to a1-acid glycoprotein. Its elimination half-life varies from 10 to 50 h, with an average of 15 h. Within 24 h, approximately 25 -- 50% of a dose of amitriptyline is excreted in the urine as inactive metabolites; small amounts are excreted in the bile [43,44]. The amitryptiline analgesic effect occurs at a dose of 25 -- 150 mg per day and shows a good response ranging between 30 and 50% [45]. It is really difficult to identify a single effective dosage because of the enormous inter-individual variability of response. Van Ophoven et al., in a prospective placebo-controlled study, found that amitriptyline significantly improved the symptom score, pain, and urgency intensity (symptom score of 8.4 for the amitriptyline group compared to 3.5 for the placebo group, p = 0.005) [46]. Even a multicenter study showed that the rate of response of subjects, receiving amitriptyline plus an educational and behavioral program, was 55%, but without significant difference compared to placebo (45%; p = 0.12). Nevertheless, in the subgroup of subjects who were able to achieve and maintain a daily dose of study drug of at least 50 mg per day, the responder rate was significantly greater in the amitriptyline group (77%) compared to placebo (53%; p < 0.001) [47]. Furthermore, Sator-Katzhenschlager compared the efficacy of amitryptiline, gabapentin, and their combination in an open-label randomized controlled trial. All patients experienced significant pain relief during the observational period (p < 0.0001). However, monotherapy with amitriptyline was associated with less pain relief compared to the other two treatment approaches [48]. Amitriptyline represents a safe and effective treatment for IC in the long-term administration, with bearable side effects and low withdrawal symptoms in most studies. Indeed, patients are usually treated with amitriptyline for at least 3 months. The initial dosage of 25 mg per day is usually increased of 25 mg though 1-week intervals if the efficacy is still poor and side effects are not observed. Hanno et al. treated, for the first time, 25 patients with IC/BPS in non-consecutive case series with amitriptyline. Initial dosage of 25 mg per day was increased gradually during a 3-week period to 75 mg per day. A significant improvement both in pain and daytime frequency was reported (p < 0.05) [49]. If the patients experienced satisfactory relief from their symptoms, they were asked to maintain the individual lowest effective dose and to not increase the dose further (Table 2) [50]. 678

Tachyphylaxis with amitriptyline is a well-known clinical problem with a losing of its clinical efficacy after 3 months [51]. Anticonvulsant Gabapentin is a structural analogue of g-aminobutyric acid of importance; it was first introduced as an anticonvulsant in 1994 and has been effectively used in various chronic pain treatments since 1960. It is especially good for treating lancinating or burning pain, allodynia, and hyperesthesia [52,53]. Gabapentinoids act as neuromodulators by selectively binding to the a2-d-subunit protein of calcium channels in various regions of the brain and the superficial dorsal horn of the spinal cord. They also have peripheral analgesic action [54]. The use of gabapentin in IC is supported by reports that this syndrome contains both a paleospinothalamic and neospinothalamic mechanism of pain. The first is responsive to narcotic therapy, but the second mechanism typically defies conventional pain therapy and is responsive to antiepileptic and antidepressant drugs [55]. Gastrointestinal absorption of gabapentin is more efficient in the upper small intestine, that is, duodenum and jejunum, than in the colon, and bioavailability decreases as the dose increases. A study on epilepsy shows that the average bioavailability of a 600 mg oral dose of gabapentin is 49%, but it may vary greatly between individuals (5 -- 74%), especially in female in which the bioavailability variability is double than that of their male counterparts (31.8 vs 15.1%) [56]. Regarding these concerns, pregabalin has a better bioavailability and pharmacodynamics profile; it is associated to a better clinical effectiveness, although there are few clinical trials about its use in IC [57]. Gabapentin is highly unbound to plasma proteins (fraction of unbound is 0.97), with an apparent volume of distribution larger than the total body water, suggesting that it distributes to the tissues. As a centrally acting drug, gabapentin penetrates into the CNS with steady-state trough concentration in the cerebral spinal fluid of ~ 20% of that in the plasma. The elimination half-life of gabapentin is ~ 6 h and is independent of dose. Renal clearance of intact gabapentin accounts for ~ 70% of the total clearance and is most likely mediated via glomerular filtration [58]. Gabapentin is generally safe and well tolerated. The most common adverse effects are dizziness (24 gabapentin vs 8% placebo) and somnolence (14 vs 5%, respectively) [59]. It is recommended that gabapentin is started at 300 mg per day on day 1 and increased by 300 mg per day to achieve a dose of 900 mg per day by day 3, with further dose increases up to 1800 mg per day by day 14. Once this dose level is achieved, gabapentin can be titrated up to 3600 mg per day as required over the following weeks to achieve a maximal response with good tolerability (Table 2) [60]. Serpell showed that mean daily pain scores were significantly reduced with gabapentin compared with placebo (p = 0.048); pain decreased by 21% in the gabapentin group 4.2



Table 2. Current antidepressant drugs in the management of interstitial cystitis/bladder pain syndrome. Drug

Start dosage

Increase dosage

Therapeutic dosage

Adverse effect

Amitriptyline Gabapentin Duloxetina

25 mg 300 mg 60 mg

25 mg per week 300 mg per week* 60 mg per week

25 -- 150 mg per day 2400 -- 3600 mg per day* 120 -- 400 mg per day

Drowsiness, fatigue, dizziness, dry mouth Dizziness, somnolence, and drowsiness Nausea, dry mouth, constipation, diarrhea, headache, somnolence/dizziness, insomnia, hyperhidrosis, palpitations and anorexia

Venlafaxina

25 mg

25 mg per week

150 mg per day


*Generally administrated in 3 divided doses.

and by 14% in the placebo group in a population with a neuropathic pain syndromes. The difference in pain between groups was statistically significant as early as the first week after the initiation of treatment (p < 0.05), when patients were receiving gabapentin 900 mg per day [59]. Moreover, Hansens reported that patients with IC/BPS improved functional capacity within their activities of daily living and received adequate pain control with the addition of gabapentin to their medication regimen. Therefore, gabapentin, as an adjunctive agent, may reduce use of cotherapeutics such as narcotics [61]. Selective serotonin norepinephrine reuptake inhibitors

4.3

Duloxetine is a selective dual serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor (SNRI) with central analgesic properties. Preclinically, duloxetine is efficacious in models of persistent, inflammatory, and neuropathic pain, suggesting that it may be efficacious in the treatment of chronic pain conditions, including IC/BPS, in which central sensitization is believed to be one of the underlying pathophysiological mechanisms. Central sensitization is related both to uncontrolled peripheral nociceptive inputs and/or to the activation/inhibition of noradrenergic descending pain facilitatory pathway. Duloxetine by enhancing monoaminergic tone, may potentially reduce the consequences of central sensitization by shifting the descending pain modulatory pathway from a state of facilitation to a state of inhibition [62,63]. Following oral administration, duloxetine is well adsorbed in the small intestine and achieves a maximum plasma concentration ~ 6 h after dosing. The absolute oral bioavailability ranges from 30 to 80%. The elimination half-life of duloxetine is 10 -- 12 h and therefore steady state occurs within 3 days. Duloxetine is extensively distributed throughout the body, as indicated by a large mean of volume of distribution of 1620 -- 1800 l [64]. In vitro studies showed that > 90% of duloxetine is protein bound in human plasma. The binding occurs primarily to albumin and a1-acid glycoprotein. Besides, duloxetine has been shown to distribute into brain areas. Duloxetine undergoes extensive metabolism, including oxidation, methylation, and conjugation. The two major circulating metabolites of duloxetine are the

glucuronide conjugate of 4-hydroxy duloxetine and the sulfate conjugate of 5-hydroxy-6-methoxy duloxetine, which are pharmacologically inactive compounds. About 72% of duloxetine is excreted in urine principally as the glucuronide and/or sulfate conjugates of the oxidative duloxetine metabolites, while fecal excretion is not a major elimination pathway (< 5% of the drug by 96 h after dosing). Therefore, severely impaired renal function warrants specific warnings or dose recommendations, such as impaired hepatic function. It is also important to be knowledgeable about the potential for PK interactions between duloxetine and drugs that inhibit CYP1A2 or drugs that are metabolized by CYP2D6 enzymes [65]. Despite the expectation regarding the outcomes of this kind of treatment, Van Ophoven and Hertle conducted a prospective case series, in which a total of 48 women were treated for 2 months following an uptitration protocol to the target dose of 40 mg taken twice daily, but the treatment did not result in statistically significant improvement of pain and urgency. Moreover, the tolerability of the drug was poor, mainly due to nausea (Table 2) [66]. In light of the current results, further studies about the use of duloxetine for IC/BPS are needed. Venlafaxine is another SNRI that showed to be effective in neuropathic pain. The mechanisms of analgesic action of venlafaxine are still poorly understood. An early research showed that venlafaxine increases the amount of NE and 5-HT in the descending inhibitory pathways at the supraspinal and spinal levels. However, the other mechanisms of analgesic action can be involved, such as NMDA receptor blockade, activation of the adenosine anti-nociceptive system, sodium channel blockade, and activation of µ- and d-opioid receptors [67]. Venlafaxine is well absorbed in the gastrointestinal tract, with at least 92% of an oral dose being absorbed into systemic circulation. It is extensively metabolized in the liver via the CYP2D6 isoenzyme to desvenlafaxine (O-desmethylvenlafaxine), which is just as potent as serotonin-norepinephrine reuptake inhibitor as the parent compound. Steady-state concentrations of venlafaxine and its metabolite are attained in the blood within 3 days. The antinociceptive effects of venlafaxine depend on the administered doses. In low doses (< 10 mg/kg), it exhibits


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properties of selective 5-HT reuptake inhibitor; at higher doses (between 10 and 100 mg/kg), it has properties of dual reuptake inhibitor. Furthermore, tolerance to the antihyperalgesic effect did not develop after long-term treatment (Table 2). This observation could have clinical relevance because this type of prolonged treatment correlates with the recommendation for therapeutic use of this drug [68]. Therapeutic effects are usually achieved within 3 -- 4 weeks. No accumulation of venlafaxine has been observed during chronic administration in healthy subjects. The primary route of excretion of venlafaxine and its metabolites is via the kidneys. The half-life of venlafaxine is relatively short (4 h), so patients are directed to adhere to a strict medication routine, avoiding missing a dose [69,70]. For SNRIs only uncontrolled studies of importance were identified. These studies have the lowest level of evidence and no firm conclusions for the efficacy of these antidepressants agents can be extracted [66,71,72]. NSAIDs and opioids Since inflammation plays a crucial role in IC/BPS pathophysiology, analgesics, such as paracetamol and NSAIDs, are strongly recommended [73]. The NSAIDs act by blocking the production of prostaglandins. NSAIDs can be divided into non-specific COX inhibitors and COX-2 specific inhibitors, the latter being selective for the cyclo-oxygenase that are expressed predominantly during inflammatory processes. NSAIDS with more selectivity toward COX-2 enzyme represent, therefore, ideal drugs for the control of acute nociceptive inflammatory pain because they can accelerate healing of the inflammatory process which generates and/or maintains pain. Nevertheless, it is important to consider that these could be associated with an increased risk of serious gastrointestinal adverse effects and cardiovascular adverse events if used for prolonged periods. Considering their PK and pharmacodynamics patterns, it is important to choose NSAIDs with more activity with COX-2 inhibition all the time that inflammation is active. Opioids are a class of drugs that relieve pain by binding to and blocking specific receptors located in the brain and spinal cord. Even if opioids have been used for thousands of years to treat pain, scientific evidence for long-term effectiveness or safety of opioids in chronic pain has not yet been fully elucidated [74,75]. Very little data are available on differences in prevalence or severity of side effects associated with different types of opioids considering their different mechanisms of action [76]. Long-term treatment of IC/BPS with opioids should be managed by specialized physicians, with special regard to the effects of opioid medications on the hypothalamicpituitary-gonadal axis. Moreover, clinical effectiveness of opioids is limited by tolerance and hyperalgesia. Chronic opioid therapy could also paradoxically induce or sensitize patients worsening pain, a condition defined opioid-induced hyperalgesia. 4.4

680

Tolerance, which is a loss of analgesic potency, is one of the common complications of opioid treatment, leading to everincreasing dose requirements and decreasing effectiveness over time. Most opioids are metabolized by glucuronidation or by the P450 (CYP) system. There is also evidence that polymorphism in the OPRM1 gene might also contribute to the wide variation in opioid sensitivity [77]; COMT variability has also been implicated in analgesic response [78]. CYP3A4 is the isoenzyme most frequently involved in drug metabolism, and accounts for ~ 50% of marketed drug metabolism; levels of CYP3A4 may vary as much as 30-fold between individuals. CYP2D6, another common catalyst for drug metabolism, accounts for < 5% of hepatic isoenzyme content but participates in the clearance of 25% of medications [79]. About 7 -- 10% of Caucasians have poor CYP2D6 metabolism [80], whereas 1 -- 7% of Caucasians and > 25% of Ethiopians have gene duplications and are classified as having ultrarapid metabolism. Morphine is metabolized by demethylation and glucuronidation, producing morphine-6 glucuronide (M6G) and morphine-3 glucuronide (M3G) in a ratio of 6:1, while ~ 5% of the drug is demethylated into normorphine. Even if drug--drug interactions with morphine are considered rare, drugs that inhibit the UGT2B7 pathway, such as carbamazepine, TCAs, and benzodiazepines, may alter the amount of M3G and M6G available; these interactions may not be clinically significant [81]. UGT2B7 variants have been shown to be related to altered drug metabolism and disease risk [82]. Hydromorphone is primarily metabolized via UGT 1A3, UGT 2B7, and dihydromorphone ketone reductase, and undergoes minimal CYP450 metabolism. Tramadol and, the more recent, tapentadol, are µ-opioid receptor agonists that also act blocking the re-uptake of neurotransmitters. Tramadol is a weak opioid that also blocks the reuptake both of noradrenaline and 5HT [83]. Tramadol is generally well tolerated and has been evaluated for the treatment of chronic neuropathic pain, painful diabetic neuropathy, and polyneuropathy [84-86]. Its use is not recommended in association with drugs acting on serotonin reuptake such as SSRIs [87]. Tramadol is metabolized via the enzyme system CYP 2D6, hence its use should be carefully monitored to avoid PK interactions. Moreover, ‘poor metabolizers’ (5 -- 15% of the population) will not experience a satisfactory pain relief with standard doses of tramadol. It is thought that in situations of chronic pain, excitatory 5HT3 receptors in the spinal cord become the preferential target of descending serotonergic pathways, resulting in an augmented pain state; thus this hypothesis represents a good reason for separating 5HT reuptake inhibition from noradrenaline reuptake inhibition [88,89]. Tapentadol is a recently developed centrally acting analgesic with two mechanisms of action: µ-opioid receptor agonism and norepinephrine reuptake inhibition in a single molecule [90]. Tapentadol is metabolized predominantly by UGT1A9 and UGT2B7; thus its metabolism guarantees a




safer PK profile. Several trials showed that tapentadol provides effective analgesia in different pain conditions (chronic low back pain, osteoarthritis pain) with a better gastrointestinal tolerability. Its effectiveness has been also investigated in neuropathic pain conditions with good results [91,92]. Hence, tramadol and tapentadol could be really helpful in all clinical settings in which a central sensitization could be involved in order to potentiate descendent inhibitory pathways. Nevertheless, there are no studies that actually prove the efficacy of these drugs in the treatment of IC/BPS. 5.

Expert opinion

Considering the complex pathophysiology of IC/BPS and the possible presence of more than one mechanism sustaining chronic pain syndromes, a correct approach should consider a multidisciplinary team of specialists and a multimodal treatment package, including psychotherapy, behavior change, physical activation, and analgesic treatment. At current knowledge, a single treatment is often ineffective by itself, since IC/BPS has very different clinical features and therefore the therapeutic approach is usually different for each patient. For a better treatment of this kind of patients, we should also evaluate the psychological, relational, and sexual aspects. Furthermore, IC/BPS is often a gender-disease and symptoms are probably linked to hormonal cycle. This is why we strongly believe that the multidisciplinary team should be composed of an urologist, a gynecologist, a sexologist, an anesthetist specialized in pain relief, a psychologist, and a physiotherapist. Unfortunately, a single therapeutic target for IC/BPS is not yet known. As regards pathophysiology and therapy, more should be discovered. Certainly, the first insult damages the bladder urothelium, hence vehicles that lead the drug to penetrate the wall of the bladder might be a novel strategic approach. Liposomes are really promising in this field. Liposomes can be described as vesicles composed of concentric phospholipid bilayers separated by aqueous compartments [93]. The walls of liposomes are made of layers of phospholipids identical to the phospholipids that compose cell membranes, which explains their biocompatibility and lack of biological toxicity. The ability of liposomes to adsorb

on cell surfaces and fuse with cells has made them a favorable choice for topical drug carriers. Liposomes seem to have an innate ability for tissue repair due to their capacity to bind water and form a molecular film on cell surfaces. Liposomes provide a moisture film on the wound and promote wound healing without chronic inflammatory reaction in the neodermal layer. Intravesical liposomes treatment revealed as a safe and effective option for IC/BPS [94], but large-scale, placebocontrolled studies are warranted to assess the efficacy for this promising new treatment for IC/BPS. Moreover, research focused on the potential of biofilms as a part of the pathogenic mix that cause most or all chronic ‘autoimmune’ and inflammatory diseases. Biofilm development, therefore, may play a role in the pathogenesis of this condition, it is likely that further studies would help to shed light on this issue. In fact, thanks to biomedical research it is now increasingly understood that chronic inflammatory diseases result from infection with a large microbiota of chronic biofilm and L-form bacteria (collectively called the Th1 pathogens). The microbiota is thought to be comprised of numerous bacterial species, some of which have yet to be discovered. However, most of the pathogens that cause inflammatory disease have one thing in common -- they have all developed ways to evade the immune system and persist as chronic forms that the body is unable to eliminate naturally [95]. Nowadays, accumulating data indicate that the gut microbiota also communicates with the CNS -- possibly through neural, endocrine, and immune pathways -- and thereby influences brain function and behavior. Studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic bacteria or antibiotic drugs suggest a role for the gut microbiota in the regulation of anxiety, mood, cognition, and pain [96]. Thus, the emerging concept of a microbiota--gut--brain axis highlights that modulation of the gut microbiota may be a tractable strategy for developing novel therapeutics for complex CNS disorders: time will determine whether this view will also apply to IC/BPS.

Declaration of interest The authors have no competing interests to declare and have received no funding in preparation of the manuscript.


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Affiliation Barbara Gardella1 MD, Daniele Porru2 MD, Massimo Allegri3 MD, Stefano Bogliolo†1 MD, Anna Daniela Iacobone1 MD, Cristina Minella3 MD, Rossella Elena Nappi1 MD PhD, Simone Ferrero4 MD PhD & Arsenio Spinillo1 MD PhD † Author for correspondence 1 University of Pavia, Fondazione IRCCS, Policlinico San Matteo, Department of Obstetrics and Gynecology, 19 Viale Camillo Golgi, 27100 Pavia, Italy Tel: +390382503722; Fax: +390382503885; E-mail: [email protected] 2 Fondazione IRCCS Policlinico San Matteo, Department of Urology, Pavia, Italy 3 University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pain Therapy Service, Pavia, Italy 4 University of Genoa, IRCCS San Martino Hospital and National Institute for Cancer Research, Department of Obstetrics and Gynecology, Genoa, Italy

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