Complementary therapies for bladder pain syndrome: a systematic review

Introduction and hypothesis Bladder pain syndrome is a difficult condition to treat. The purpose of this systematic review is to assess the effectiveness of various complementary therapies available for treatment. Methods This review was conducted in adherence with Preferred Reporting Items for Systematic Reviews. Citations were retrieved using a comprehensive database search (from inception to July 2014: CINAHL, Cochrane, EMBASE, Medline and SIGEL and grey literature). Studies that fulfilled the inclusion criteria were selected. Eligibility consisted of women with bladder pain syndrome, an intervention of alternative/complementary therapies and an outcome of improvement of symptoms. Information regarding study characteristics and primary outcomes was collated. The Cochrane risk of bias scale was used to evaluate the quality of the studies included. Results A total of 1,454 citations were identified, 11 studies fulfilled the inclusion criteria (4 randomised control trials [RCTs] and 7 prospective studies). The key interventions studied were acupuncture, relaxation therapy, physical therapy, hydrogen-rich therapy, diet and nitric oxide synthetase. Conclusion Therapies with the potential for benefit in patients with bladder pain syndrome are dietary management, acupuncture and physical therapy. These findings were obtained from small studies and hence caution is advised. Robustly designed multicentre RCTs on these complementary therapies are needed to guide patients and clinicians.


Introduction
The European Society for the Study of Interstitial Cystitis/ Bladder Pain Syndrome in 2008 defined bladder pain syndrome (BPS) as pelvic pain, pressure or discomfort perceived to be related to the bladder, lasting for at least 6 months, and accompanied by at least one other urinary symptom [1]. Urinary symptoms include the persistent urge to void or frequency, in the absence of other identifiable causes. The International Urogynaecological Association (IUGA) and the International Continence Society (ICS) produced a joint report on terminologies by Haylen et al. in 2010, defining bladder pain as a Bcomplaint of supra pubic or retro-pubic pressure, discomfort or pain, associated with the bladder, generally aggravated by bladder filling. The symptom may persist or alleviate after voiding.^ [2]. An estimated 400,000 people in the UK suffer from BPS, the majority being women [3]. There is no definitive evidence to support an autoimmune, inflammatory, structural or infectious aetiology. Consequently, treating these patients is often challenging.
The interest in complementary and alternative therapies among patients is high and the number of effective treatments available for BPS are few [4]. Complementary and alternative therapies are an essential addition to the therapeutic armamentarium and include dietary modification, bladder training, acupuncture and stress reduction [5]. In 1995, complementary and alternative medicine (CAM) was defined by the National Institutes of Health (NIH) Center for Complementary and Alternative Medicine as, those treatments and healthcare modalities not widely taught or practised in medical schools or hospitals, and not usually reimbursed by medical insurance companies [6].
Our aim was to conduct a systematic review to evaluate the effectiveness of complementary therapies in the treatment of BPS.

Materials and methods
This review was planned, conducted and reported in adherence with widely recommended methods [7]. No ethical approval was needed.

Identification of studies
The following bibliographic databases were searched, from database inception to July 2014: CINAHL, Cochrane, EMBASE, Medline and SIGEL. Search strategies consisted of MeSH subheadings, text words and word variations for the concepts of BPS and alternative/complementary therapies. The basic search strategy was adapted to suit the database being searched. Librarians [8] to store all references identified. No language restrictions were applied.

Study selection and data extraction
Studies were selected following a two-step process. Firstly, the citations identified by the electronic bibliographic database searches were screened, based on their titles and abstracts. Full text papers of eligible abstracts were retrieved. Once full text papers had been located, we determined whether they fulfilled our predetermined inclusion criteria: Population: women with BPS or interstitial cystitis (IC). Intervention: complementary or alternative therapies Comparator: no treatment, another therapy Outcome: improvement in bladder symptoms Study designs: randomised controlled trial (RCT), cohort studies, case control studies, case series Exclusion criteria: pharmacological therapy, intravesical therapy, hydrodistention, tibial nerve stimulation Two reviewers (TV, RNR) independently assessed the full text papers to determine if they met the above criteria. Any disagreements regarding the eligibility of a paper were solved through either consensus or arbitration by a third reviewer (PML). Data from the manuscripts included were extracted independently onto a pre-designed pro-forma. The literature search was thorough and without language restrictions. The grey literature was also searched and the data were extracted by two reviewers independently to reduce bias.
Data were collated on study characteristics, including methods of recruitment, patient characteristics, details of complementary therapy, outcomes and results. We contacted primary authors via email for any further information/ clarification that was needed.

Methodological quality
The methodological quality of all the papers fulfilling the inclusion criteria was assessed. Quality was defined as the confidence that the study design, conduct and analysis minimised bias in the estimation of effectiveness. Quality was assessed using existing checklists and scales [9,10].
The methodological quality of the RCTs included was assessed using the Cochrane risk bias score [9]. The methodological quality of the non-RCT studies included was assessed using the Newcastle-Ottawa scale [10], where a nonrandomised study was considered to be of high quality if it provided information on selection, comparability, exposure and outcome of the study participants. The quality checklist awards one star as a maximum for all items except comparability, where a maximum of two stars can be awarded. The scale was used to give a quantitative appraisal of overall quality of the non-randomised studies. The score ranged from 0 to 9, with a score of either 0 or 1 for each item.

Data synthesis
We grouped studies according to their type of intervention and the comparison. The comparisons were with no intervention, with placebo or with another intervention. The outcome measures were based on the responses from questionnaires such as the Visual Analogue Score (VAS) [11], the Interstitial Cystitis Symptom Index (ICSI)/O'Sant Leary questionnaire [12], the Interstitial Cystitis Problem Index (IPSI) [12] and the maximum voided volume (MVV) on the frequency volume chart.

Results
Out of the 1,454 citations identified by electronic literature searches, 11 studies that fulfilled the inclusion criteria were included in the systematic review (Fig. 1); 4 were randomized controlled trials (RCTs) and 7 were prospective studies. Table 1 provides a summary of the characteristics of the studies included. The mean age of the women ranged between 43 and 64 years. The criteria for the diagnosis of BPS varied in the studies included. Some studies diagnosed BPS clinically based on bladder pain scale, frequency and urgency. Other studies confirmed PBS based on the cystoscopic and hydrodistention findings. Because of the varied definitions utilised in last 5 years, we set the inclusion criteria for women with a diagnosis of BPS to be based on one of the following definitions: Hanash and Pool [13,14], Messing and Stamey [15], the ICS [2] or NIH criteria [16], or the ESSIC definition (Table 1) [1]. Outcomes were documented as per the symptom-specific scores (VAS score, ICSI and ICPI). Tables 2 and 3 provide details of the methodological quality of the RCTs included. Table 4 summarises details of the quality of the non-randomised studies included.  38 % of women showed improvement in symptoms after 3 months [19]. In a study conducted at the University of Tennessee, 20 patients with IC were hypnotised every 2 weeks for 2 months. Outcomes measured were a reduction in the analgesic requirements, increase in sleep time and quality of life (QoL). The majority of patients (95 %; 19 out of 20) were amenable to hypnotherapy and subsequently experienced pain reduction. Five patients reported a significant improvement (8-10 to 0-1 out of 10) on VAS and 85 % (n=17 out of 20) were able to reduce their intake of analgesics by 25-50 % [20]. Carrico et al. conducted a pilot RCT in which more than 45 % of the treatment group responded to Bguided imagery^, with a moderate or marked improvement in the global response rates (Table 1). In addition, the treatment group had a significant reduction in their ICSI (p=0.006) and ICPI scores (p=0.004) [21].

Hydrogen-rich therapy
Matsumoto et al. conducted an RCT (30 women) of hydrogenrich water versus placebo water for 2 months. The authors describe the process of the production of hydrogen-rich water. This was produced by passage through a reverse osmosis, an ion-exchange resin, and an ultrafiltration membrane. Hydrogen-rich pure water was then produced from dissolving hydrogen gas directly into pure water. To prevent the loss of hydrogen, the water is sealed in aluminium pouches and stored at room temperature. The study demonstrated no significant differences between treatment and placebo (Table 1) [22].

Physical therapy
FitzGerald et al. conducted a multicentre RCT (n=81 women) to determine the efficacy of myofascial physical therapy (MPT) compared with global therapeutic massage (GTM) [23]. The MPT group underwent connective tissue manipulation to all body wall tissues of the abdominal wall, back, buttocks and thighs that were clinically found to have connective tissue abnormalities to painful myofascial trigger points. Manipulation was applied bilaterally with the patient in the prone and then repeated in the supine position. This was performed until a texture change was noted. Manual trigger point release techniques were utilized to treat any noted trigger points or scars in the anterior or posterior lower quadrants. In the MPT arm, the therapists tailored the therapy to target patient needs.
Patients randomised to the GTM group received weekly massages consisting of full-body Western massage for 1 h. The therapist utilised techniques such as effleurage, petrissage, friction, tapotement, vibration and kneading.
At the end of 12 weeks, the global response rate was 26 % in the GTM group and 59 % in the MPT (p=0.0012) group. Both groups reported improvement in secondary outcomes, including pain, urgency, frequency and QoL [23].
Similarly Ervan et al. conducted a non-randomised study on women with BPS. The physical therapy included connective tissue mobilisation over the trunk, thighs, buttocks and the release of trigger points, the resolution of adverse neural tension along the pudendal nerve, rehabilitation of the pelvic floor and hip girdle musculature. ICSI scores fell from median range of 12 before treatment to 6 post-therapy (p<0.001). The ICPI scores decreased from 10 to 7 after therapy (p<0.001) [24].
Women with BPS tend to have hypertonic pelvic floor muscle dysfunction. In these women, a combination of transvaginal biofeedback and transcutaneous electric nerve stimulation for more than 2 months has not been shown to have a long-term beneficial effect [25].

L-arginine
Korting et al. undertook an RCT to investigate the efficacy of L-arginine, which is a substrate for nitric oxide, in which there were no differences between the groups according to intention-to-treat analysis (Table 1) [26].
Ueda et al. in their prospective study administered citrates to elevate the urine pH (Table 1). Urine alkalinisation was shown to be effective at improving symptoms of BPS [27].
Sacral acupuncture is a safe and promising therapeutic alternative, particularly in patients with PBS who have symptoms that do not respond to conventional treatments [17]. Acupuncture inhibits the transmission of pain and normalizes sensory processing within the peripheral and/or central nervous system. Patients with BPS display tension and tenderness of the pelvic floor musculature and connective tissue restrictions of muscle, fascia and subcutaneous tissue of the pelvic floor. Physical therapies, such as MPT, were found to be beneficial in women with symptoms of BS and associated pelvic floor tenderness [23].

Discussion
To date there has been a paucity of studies addressing the effectiveness of complementary therapies in BPS. Results obtained from the small-scale studies we reviewed must be considered with caution because of the number of participants. Moreover, the definition of BPS in various studies is not uniform. Several unanswered questions regarding complementary therapies exist including, its applicability to all patients with BPS and the costeffectiveness of treatment. The majority of studies reviewed undertook a limited period of follow-up prohibiting analysis of the long-term efficacy of the treatment. Studies evaluating the role of tibial nerve stimulation were excluded, as this has been explored in a recent systematic review [28].
The studies included did not discuss details of adverse effects of complementary therapies. However, in 2009 a group of CAM researchers conducted a workshop to discuss the challenges and safety issues of CAM. They found a low incidence of harmful/ serious side effects from CAM [29]. Prospective observational studies have been conducted to evaluate the harmful effects of acupuncture; it has been found to be relatively safe. The data from 2.2 million treatment sessions found a risk of harmful events to be 1 in 76,000 patients [30]. The most common side effects noted with acupuncture were minor, e.g. bleeding or haematoma.
Shorter et al. utilised a validated questionnaire (IC/nutrition questionnaire) in a survey to detect whether food, beverages and supplement affect bladder symptoms in patients with BPS [31]. Analysis of the scoring of individual comestible items revealed that most bothersome consumables were caffeinated, carbonated and alcoholic beverages, citrus fruits and juices, artificial sweeteners and spicy foods. These results were obtained from survey rating and therefore further research and studies are required for confirmation of the results of the surveys conducted. Relief of symptoms was noted following ingestion of alkaline agents, e.g. calcium glycerophosphate (Prelief®) or sodium bicarbonate (baking soda). Interestingly, 75 % of respondents indicated that they had allergies, including seasonal allergies, allergies to medications, animals or foods. The survey conducted on female twins (n=9,349) found that tea consumption was associated with an increased risk of BPS (OR 1.74, 95%CI 1.24-2.44), although coffee consumption was not (OR 1.1, 95%CI 0.84-1.45) [32]. Former and current smoking was associated with a higher risk of BPS (OR 1.5, 95%CI 1.18-1.89 and OR 1.49, 95%CI 1.16-1.92 respectively) [33]. *Indicates that a feature is present; x, that a feature is absent. But for comparability by design this checklist awards a maximum of two stars (**), one (*) or none if the feature is completely absent (x) In 2009, the Interstitial Cystitis Association (ICA) conducted an Internet-based survey of complementary therapies. A total of 2,101 responded to the survey; 1,982 confirmed an IC diagnosis. 84.2 % had tried complementary therapies and 55 % said that physicians had recommended complementary therapies [4]. Therapies perceived to be helpful included dietary management, myofascial physical therapy, temperaturerelated therapies, acupuncture, stress reduction and exercise. Some supplements, such as calcium glycerophosphate (Prelief), vitamin D, fish oil and probiotics, were also considered to be helpful. Calcium glycerophosphate appears to reduce BPS symptoms in a patient whose symptoms are exacerbated by particular foods [34]. Tettamanti et al. reported their findings from a population-based study demonstrating that tea and smoking were positively associated with BPS [33].
Many interstitial cystitis (IC) patients resort to nonconventional therapies after the failure of conventional measures. Unfortunately, little research on complementary and alternative therapies in the treatment of IC exists [5] and this is confirmed by our systematic review. Complementary and alternative medical therapy for interstitial cystitis (IC) is multimodal and individualized. Patients should be advised about the lack of robust evidence on complementary therapies and encouraged to participate in on-going studies on various therapies related to BPS [35].
In view of the dearth of robust evidence, there is a need for adequately powered RCTs to assess the effectiveness of complementary therapies in women with BPS. Studies could focus on therapies demonstrating potential with the limited evidence to date including: L-arginine, acupuncture, hypnotherapy and dietary modifications.