Comparative effectiveness and safety of cocktail therapy versus combined sodium hyaluronate and chondroitin sulphate (Ialuril): Intravesical instillation treatment of interstitial cystitis/bladder pain syndrome,which one to use?

Abstract

Objective:

To compare effectiveness and safety of intravesical therapy (sodium hyaluronate and chondroitin sulphate) Ialuril versus cocktail therapy for treatment of interstitial cystitis (IC).

Materials and methods:

Prospective study from March 2013 till August 2019 including all IC patients presented to our urology clinic. All IC patients underwent basic workup including urine test, urodynamic test and gynaecological/genital exam. Postoperatively, all patients received intravesical therapy. Patients were randomly allocated to either cocktail therapy (NaOH + heparin + lidocaine) or Ialuril (Sodium hyaluronate and chondroitin sulphate) therapy as intravesical seven cycles. The primary outcome was therapy effectiveness using Interstitial Cystitis Problem Index (ICPI) and Interstitial Cystitis Symptom Index (ICSI) improvement post therapy. Secondary outcome were for complications and compliance.

Results:

Total of 32 patients were included (6 males, 26 females) with mean age of 43 years (24–72 years), mean follow-up 36 months (15–72 months). Cocktail intravesical therapy was used in 21 patients while 11 patients received Ialuril. All patients showed improvement on their ICSI and ICPI scores post therapy from their baseline. Statistical analysis showed no significant difference between both groups regarding improvement in ICSI and ICPI index with p-value = 0.552 and p = 0.79, respectively. Infection and non-compliance is significantly high in the cocktail arm p = 0.004, p = 0.027

Conclusions:

Intravesical cocktail therapy was equally effective as Ialuril in treating IC. Ialuril was preferred over cocktail therapy because of lower side effect; when considering ulcerative IC subgroup, we need large randomised controlled trials to compare therapy benefits.

Keywords

Interstitial cystitis intravesical therapy cocktail therapy therapy effectiveness interstitial cystitis compliance

Introduction

Interstitial cystitis (IC) is a chronic bladder disease of unknown aetiology. It occurs more in females and requires treatment for symptom relief.¹ Its hallmark symptom is suprapubic pain, frequency urgency pelvic and genital pain, with a major effect on patient quality of life.² IC has a wide spectrum of symptoms and severity, for which recently the terms painful bladder syndrome (PBS) or bladder pain syndrome (BPS) is used.

To date, there is an agreement on the administration of intravesical therapy.^3–6 Glycosaminoglycans (GAGs) are classified into four structural groups⁷ (heparin and heparan sulphates; chondroitin and dermatan sulphates; hyaluronan; and keratan sulphate) and have been used as intravesical instillations for GAG substitution therapy, they have the benefit of a low risk of systemic side effects.⁸ Intravesical treatment with dimethyl sulfoxide (DMSO), chondroitin sulphate (CS), hyaluronic acid and heparin have been used to repair the GAG layer with variable clinical success^5,9 Heparin has commonly been used off-label for IC/BPS therapy. Other intravesical instillations containing anaesthetic solutions, such as lidocaine and bupivacaine, are also used in combination with sodium bicarbonate to control bladder pain.¹⁰

Today, hyaluronan, the salt of hyaluronic acid (HA), and chondroitin sulphate (CS) are used for intravesical treatment, alone or in combination, while DMSO, which has a putative effect on the sensory peripheral nerves of the bladder,¹¹ is the only intravesical therapy approved by the FDA.

Sodium hyaluronate/chondroitin sulphate (HA/CS) Ialuril® is a pre-filled syringe commercially available option for intravesical therapy. Another option is the cocktail therapy, which is composed of heparin sulphate, lidocaine and sodium bicarbonate.

Aim of our study is to compare Ialuril (HA and CS) versus cocktail therapy (heparin, NAHCO₃ + lidocaine) for treatment of IC/BPS.

Materials and methods

Study design

We conducted our prospective cohort study in King Abdulaziz University Hospital, Jeddah, Saudi Arabia, from March 2013 till August 2019 including all IC/BPS patients presented to our urology clinic. The Study was performed in accordance with Helsinki declaration after obtaining ethical approval. Written informed consent was obtained from all patients for their anonymised information to be published in this article.

Study population

We included patients who were diagnosed as IC/BPS. Diagnosis of IC/BPS was made based on the clinical symptoms history of bladder pain and discomfort related to bladder filling accompanied by frequency in the absence of infection; we included patients with normal gynaecological and genital exam with clean urine analysis and culture to exclude UTI, urodynamic was done to exclude OAB, including patients with cystoscopy findings of IC. Patients meeting the NIDDK (National Institute of Diabetes, Digestive and Kidney Diseases) criteria for IC were diagnosed as having IC/BPS.¹² Including both ulcerative and non-ulcerative types.

Exclusion criteria are bladder cancer, history of genitourinary (GU) malignancy within the last 5 years, pregnant and lactating, neurogenic bladder, patients with indwelling catheters, overactive bladder chronic bacterial prostatitis, currently receiving or having had prior therapy with intravesical treatment for IC or heparin or Bacillus Calmette-Guérin (BCG), receiving antidepressants or radiation cystitis, bladder or lower ureteral calculi, active sexual transmitted disease, current vaginitis and endometriosis.

Urodynamic test

Urodynamic test was done baseline for all patients to exclude overactive bladder using International Continence Society standards.

Intervention

All study group patients underwent bladder hydrodistention, additional ulcer fulgurations for ulcerative IC patients during the hydrodistention using laser was done. Postoperatively, all patients received intravesical therapy on the second day post hydrodistention. Patients were randomly allocated to either cocktail intravesical therapy (NaOH + heparin + lidocaine) or Ialuril (HA and CS) therapy.

Patients were blinded and randomly allocated to receive either cocktail intravesical therapy (NaOH + heparin + lidocaine) or Ialuril (HA and CS) therapy. HA/CS Ialuril® is a pre filled syringe commercially available with the composition of 800 mg low molecular weight (LMW)-HA (1.6%) / 1 g CS (2%) in 50 ml normal saline. Cocktail therapy, which is composed of heparin sulphate 40,000 IU, Lidocaine 2% 8 mL sodium bicarbonate 8.4% 3 mL in normal saline to reach 50 ml, which is prepared at the time of cycle. The bladder instillation was performed by a trained medical professional using a temporary catheter under sterile technique, the bladder is emptied first and then filled with cocktail therapy or Ialuril; patients were asked to retain intravesical therapy as long as they can with minimum of 30 minutes. Both groups received a total of seven cycles of therapy, initially once a week for 4 weeks. Further instillations were given at week 6, 8 and 12.

Outcome assessment

At the clinic visit before hydrodistention, all IC/BPS patients were asked to fill up self-rated measures of O’Leary–Sant Interstitial Cystitis Symptom Index (ICSI) and Interstitial Cystitis Problem Index (ICPI) as their baseline. The follow-up of ICSI and ICPI were done 2 weeks after finishing intravesical therapy. Patients were asked to fill in the ICSI (four questions) and ICPI (four questions). The primary outcome was therapy effectiveness using O’Leary–Sant ICPI and O’Leary–Sant ICSI improvement post therapy by comparing mean difference between pre- and post-therapy index. Secondary outcome were complications specifically developing any UTI and compliance on treatment.

O’Leary–Sant ICSI and ICPI

The ICSI and the ICPI were developed in 1997 to measure lower urinary tract symptoms (LUTS) and their impact in patients with IC/BPS. They are self-administered questionnaires, which are valid and reliable to help in IC/BPS diagnosis, not screening. These indices are useful in measuring response to therapy in clinical studies. The ICSI and ICPI are composed of four questions each. Their scoring include the total sum up of each question score.^13,14

Complications

We assessed the following complications in both groups as UTI, need to repeat therapy and non-compliance. Urinary tract infection was defined as symptoms suggestive of UTI with a positive urine analysis and positive culture. Need to repeat therapy was defined as the need of intravesical instillations after 4 weeks of the last cycle. Non- compliance was defined as patient not compliant with intravesical cycles because of LUTS (without UTI) induced by intravesical therapy.

Statistical analysis

All patients demographics and data were collected into excel sheet and further analysed using software SPSS for Windows, version 26. (IBM Corp., Armonk, NY, USA). Descriptive statistics were reported as frequencies for categorical variables. Comparison between pre and post means for ICPI and ICSI was performed using t-test. Correlation analysis (two-sided Pearson with two degrees of freedom) was used between outcome results and patients’ diagnosis, and therapy-type statistical significance was considered for p-values < 0.05. Drop-outs and lost to follow-up are considered as failures.

Results

Total of 32 patients were included (6 males, 26 females) with mean age of 43 years (24–72 years standard deviation 14.98), mean follow-up 36 months (15–72 months standard deviation 33.37).

Ulcerative IC was found in 8 patients out of the 32. Patients were grouped into group 1 who received cocktail intravesical therapy total 21 patients, and group 2 received Ialuril total 11 cases, Table 1.

Table 1.

Patients demographics.

Variable	Number
Total patients	32
Age	(24–72) years, mean 43±14
Follow-up	(15–72) months, mean 36 Median 33 months
Gender
• Male	6
• Female	26
Diagnosis
• Non-ulcerative IC	24
• Ulcerative IC	8
Therapy type
• Cocktail therapy (NaOH + heparin + lidocaine)	21
• Ialuril therapy (sodium hyaluronate and chondroitin sulphate)	11
Outcome
• Improved	25
• Failure of therapy	7
Complications
Developed UTI	3
Need repeat therapy	6
Non-compliance	2

IC: interstitial cystitis; UTI: urinary tract infection.

Group 1 total (21) had 3 ulcerative IC and 18 non-ulcerative type, all received cocktail intravesical therapy and 2 cases needed to repeat therapy to maintain symptom control. Three patients developed UTI and two out of them were not compliant and needed to treat UTI and delay their intravesical therapy, five patients out of 21 had therapy failure (no symptomatic improvement).

Group 2 total (11) included those who received Ialuril intravesical, it included 6 patients with ulcerative IC type. After receiving therapy, four needed to repeat therapy to have better response.

Statistical analysis showed no significant difference between both groups regarding improvement in ICSI and ICPI index p-value = 0.552, p = 0.79, respectively. Therapy failure was reported in 2 patients out of 11.

Post-therapy scores of ICSI and ICPI in both groups did not show significant difference, infection and non-compliance is significantly high in the cocktail arm p = 0.004, p = 0.027; Figure 1, Table 2.

Figure 1.

Boxplot for (a) ICSI and (b) ICPI score pre and post therapy categorised according to type of therapy used (cocktail and Ialuril).

Table 2.

Comparison between both groups 1 and 2 regarding patient details and therapy outcome.

Variables	Group 1 Cocktail therapy (NaOH + heparin + lidocaine)	Group 2 Ialuril therapy (sodium hyaluronate and chondroitin sulphate)	p-value
Number	21	11
Mean age (9 years)	42±15	46±13	0.75
Follow-up (mean months)	31.9	36.9	0.006
Gender			0.9.8
• Male	4	2
• Female	17	9
Diagnosis			0.003
• Non-ulcerative IC	18	6
• Ulcerative IC	3	5
Therapy outcome			0.468
• Improved	16	9
• Failure	5	2
Developed UTI	3	0	0.004
Repeated therapy	2	4	0.001
Compliant to therapy	19	11	0.027
Baseline ICSI (mean)	17.95	18.36	0.843
ICSI post therapy(mean)	7.29	7.91	0.532
Baseline ICPI (mean)	15.81	15.55	0.020
ICPI post therapy (mean)	8.62	8.45	0.79

IC: interstitial cystitis; UTI: urinary tract infection; ICSI: Interstitial Cystitis Symptom Index; ICPI: Interstitial Cystitis Problem Index.

Correlation analysis showed significant correlation between IC/BPS type and need to repeat intravesical therapy p = 0.008 Pearson correlation 0.462 (ulcerative IC need repeated therapy). Ulcerative IC patients were having the worse ICSI score pre therapy p = 0.001 (Pearson correlation 0.573) and patient outcome was affected by UTI p = 0.001 (Pearson correlation 0.608).

Further subgroup analysis for therapy effect was done according to diagnosis of ulcerative and non-ulcerative IC, which did not show any significant difference between both used intravesical therapy in each diagnosis group; Figures 2 and 3, Tables 3 and 4.

Figure 2.

Boxplot for ICPI score pre and post therapy in subgroup analysis according to diagnosis categorised according to type of therapy used (cocktail and Ialuril).

Figure 3.

Boxplot for ICSI score pre and post therapy in subgroup analysis according to diagnosis categorised according to type of therapy used (cocktail and Ialuril).

Table 3.

Patient therapy groups categorised according to diagnosis IC/BPS versus ulcerative IC.

Dx		Type of therapy	N	Mean	Standard deviation	Standard error mean
IC/BPS	Age	Cocktail	18	41.72	15.578	3.672
		Ialuril	6	38.50	12.566	5.130
	Gender	Cocktail	18	1.78	0.428	0.101
		Ialuril	6	1.67	0.516	0.211
	Outcome	Cocktail	18	1.28	0.461	0.109
		Ialuril	6	1.33	0.516	0.211
	Infection	Cocktail	18	1.83	0.383	0.090
		Ialuril	6	2.00	0.000	0.000
	Need repeat	Cocktail	18	1.94	0.236	0.056
		Ialuril	6	1.83	0.408	0.167
	Patient compliance	Cocktail	18	1.11	0.323	0.076
		Ialuril	6	1.00	0.000	0.000
	f/u	Cocktail	18	31.44	4.902	1.155
		Ialuril	6	37.67	9.832	4.014
	ICSI score	Cocktail	18	17.78	0.943	0.222
		Ialuril	6	17.83	0.753	0.307
	ICPI	Cocktail	18	15.83	0.383	0.090
		Ialuril	6	15.50	0.548	0.224
	ICSI post	Cocktail	18	7.22	1.114	0.263
		Ialuril	6	7.67	1.211	0.494
	ICPI post	Cocktail	18	8.56	0.856	0.202
		Ialuril	6	8.83	0.753	0.307
Ulcerative IC	Age	Cocktail	3	49.67	13.279	7.667
		Ialuril	5	55.20	6.686	2.990
	Gender	Cocktail	3	2.00	0.000^a	0.000
		Ialuril	5	2.00	0.000^a	0.000
	Outcome	Cocktail	3	1.00	0.000^a	0.000
		Ialuril	5	1.00	0.000^a	0.000
	Infection	Cocktail	3	2.00	0.000^a	0.000
		Ialuril	5	2.00	0.000^a	0.000
	Need repeat	Cocktail	3	1.67	0.577	0.333
		Ialuril	5	1.40	0.548	0.245
	Patient compliance	Cocktail	3	1.00	0.000^a	0.000
		Ialuril	5	1.00	0.000^a	0.000
	F/u	Cocktail	3	34.67	2.309	1.333
		Ialuril	5	36.00	22.147	9.905
	ICSI score	Cocktail	3	19.00	0.000^a	0.000
		Ialuril	5	19.00	0.000^a	0.000
	ICPI	Cocktail	3	15.67	0.577	0.333
		Ialuril	5	15.60	0.548	0.245
	ICSI post	Cocktail	3	7.67	0.577	0.333
		Ialuril	5	8.20	1.304	0.583
	ICPI post	Cocktail	3	9.00	1.000	0.577
		Ialuril	5	8.00	0.707	0.316

IC: interstitial cystitis; BPS: bladder pain syndrome; F/u: follow-up; ICSI: Interstitial Cystitis Symptom Index; ICPI: Interstitial Cystitis Problem Index. a: mean no difference between both types of therapy.

Table 4.

Patient groups divided according to diagnosis and further subgroup analysis of both therapy used in each category.

Dx		t	df	Significance (two-tailed)	Mean difference	Standard error difference	95% confidence interval of the difference
Dx		t	df	Significance (two-tailed)	Mean difference	Standard error difference	Lower	Upper
IC/BPS	Age	0.457	22	0.652	3.222	7.046	−11.391	17.835
	Gender	0.524	22	0.605	0.111	0.212	−0.328	0.551
	Outcome	−0.249	22	0.806	−0.056	0.223	−0.519	0.408
	Infection	−1.049	22	0.306	−0.167	0.159	−0.496	0.163
	Need repeat	0.829	22	0.416	0.111	0.134	−0.167	0.389
	Patient compliance	0.829	22	0.416	0.111	0.134	−0.167	0.389
	F/u	−2.073	22	0.050	−6.222	3.001	−12.447	0.002
	ICSI score	−0.130	22	0.897	−0.056	0.426	−0.938	0.827
	ICPI	1.658	22	0.111	0.333	0.201	−0.084	0.750
	ICSI post	−0.829	22	0.416	−0.444	0.536	−1.556	0.667
	ICPI post	−0.707	22	0.487	−0.278	0.393	−1.092	0.537
Ulcerative IC	Age	−0.805	6	0.452	−5.533	6.873	−22.352	11.285
	Need repeat	0.655	6	0.537	0.267	0.407	−0.730	1.263
	F/u	−0.101	6	0.923	−1.333	13.242	−33.735	31.068
	ICPI	0.164	6	0.875	0.067	0.407	−0.930	1.063
	ICSI post	−0.655	6	0.537	−0.533	0.815	−2.527	1.460
	ICPI post	1.677	6	0.145	1.000	0.596	−0.459	2.459

IC: interstitial cystitis; BPS: bladder pain syndrome; F/u: follow-up; ICSI: Interstitial Cystitis Symptom Index; ICPI: Interstitial Cystitis Problem Index.

Discussion

Several types of intravesical therapy have been used in IC/BPS including heparin, lidocaine, pentosan polysulphate sodium, DMSO, CS, HA (and combined with CS)^8–11,15 and Botox.¹⁶

Heparin used in combination with lidocaine and sodium bicarbonate was reported to have a good result in 56–73% by downregulating bladder sensory nerves in IC/BPS patients.^17,18 Parsons et al.¹⁹ reported the use of alkalinised lidocaine gives immediate relief of pain and urgency 50% compared to placebo 13%. Welk and Teichman²⁰ even reported 57% complete resolution of dyspareunia in women when using cocktail therapy. So far, all reports are from small cohorts and lacking randomised controlled trials.

Combined HA and CS reported equal effectiveness to DMSO with lower side effect.^21,22 One study showed better effect with combination therapy on female sexual function in IC/BPS group in comparison to CS alone.²³ Pyo and Cho²⁴ reported systematic review and meta-analysis including 390 IC/BPS patients, which showed significant improvement with intravesical hyaluronate and combined HA and CS. Again all reports are still lacking randomised trials to compare its effectiveness to placebo.

Our study compared Ialuril (HA and CS) to heparin cocktail therapy. Most of our IC/BPS study group are females (81%), which is comparable to the disease gender distribution. Ulcerative IC type requires ulcer fulgurations, which can be done by transurethral resection or transurethral coagulation with equal results.²⁵ We used Nd: laser for ulcer fulgurations, which is reported by Rofiem et al.²⁶ to have good results without complication to ablate Hunner lesions in 24 patients. Our study showed that ulcerative IC/BPS patients had the worse baseline ICSI score.

Our instillation protocol of intravesical therapy was comparable to other reported studies. A systematic review and meta-analysis on the efficacy of intravesical therapy for IC/BPS reported the initial instillation therapy to be weekly in 73.7%, but with different follow-up schedules.¹⁵

Our study was comparing the cocktail therapy to combined HA and CS; to our knowledge, here was only one conference abstract that compared two commercial types of combined HA/CS to different composition cocktail therapy containing cortisol.²⁷ Our study showed that both Ialuril and cocktail therapy are equally effective, but the study done by Cocci et al.²⁷ reported that the cocktail therapy was the most cost-effective option when compared to other combined HA/CS. Unfortunately cost-effectiveness analysis was not done in our study.

Our study showed that ulcerative IC patients required repeated cycles to control their symptoms and that UTI affected patient therapy compliance.

Limitations of our study are mainly the small sample size (not well powered) and discrepancy of case number between both groups. Another limitation is short follow-up and the lack of a placebo control group to evaluate placebo effect, while randomisation of IC patients to placebo group may be difficult with their severe pain. The patient characteristic is different between treatment groups, a lot of patients in Ialuril therapy group are ulcerative type IC, despite doing subgroup analysis but large randomised controlled trials to compare therapy benefits are needed

Conclusion

Footnotes

Conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

Ethical approval was obtained from King Abdulaziz Hospital ethical research committee (No 410-20).

Informed consent

Written informed consent was obtained from all patients for their anonymised information to be published in this article.

ORCID iD

Mai Ahmed Banakhar

References

Hanno

. Interstitial cystitis and related disorders. In: Walsh

Retik

Vaughan

ED Jr

, et al. (eds) Campbell’s urology, vol 1. 8th ed. Philadelphia, PA: WB Saunders, 2002, pp. 631–670.

Michael

Kawachi

Stampfer

, et al. Quality of life among women with interstitial cystitis. J Urol 2000; 164: 423–427.

Engeler

Baranowski

Dinis-Oliveira

, 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: 431–439.

Hanno

Erickson

Moldwin

, et al. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J Urol 2015; 193(5): 1545–1553.

Daha

Lazar

Simak

, et al. The effects of intravesical pentosanpolysulfate treatment on the symptoms of patients with bladder pain syndrome/interstitial cystitis: Preliminary results. Int Urogynecol J Pelvic Floor Dysfunct 2008; 19(7): 987–990.

Daha

Riedl

Lazar

, et al. Effect of intravesical glycosaminoglycan substitution therapy on bladder pain syndrome/interstitial cystitis, bladder capacity and potassium sensitivity. Scand J Urol Nephrol 2008; 42(4): 369–372.

Madersbacher

van Ophoven

van Kerrebroeck

PEVA

. GAG layer replenishment therapy for chronic forms of cystitis with intravesical glycosaminoglycans – A review. Neurourol Urodyn 2013; 32: 9–18.

Von Heyden

Schmid

. Intravesical therapy of interstitial cystitis. Urologe A 2000; 39: 542–544.

Riedl

Engelhardt

Daha

, et al. Hyaluronan treatment of interstitial cystitis/painful bladder syndrome. Int Urogynecol J Pelvic Floor Dysfunct 2008; 19(5): 717–721.

10.

Nickel

Moldwin

Lee

, et al. Intravesical alkalinized lidocaine (PSD597) offers sustained relief from symptoms of interstitial cystitis and painful bladder syndrome. BJU Int 2009; 103: 910–918.

11.

Parkin

Shea

Sant

. Intravesical dimethyl sulfoxide (DMSO) for interstitial cystitis – A practical approach. Urology 1997; 49: 105–107.

12.

Gillenwater

Wein

. Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases workshop on interstitial cystitis, National Institutes of Health, Bethesda, Maryland, August 28-29, 1987. J Urol 1998; 140: 203–206.

13.

O’Leary

Sant

Fowler

Jr , et al. The interstitial cystitis symptom index and problem index. Urology 1997; 49(5A, Suppl.): 58–63.

14.

Lubeck

Whitmore

Sant

, et al. 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): 62–66.

15.

Barua

Arance

Angulo

, et al. A systematic review and meta-analysis on the efficacy of intravesical therapy for bladder pain syndrome/interstitial cystitis. Int Urogynecol J 2016; 27(8): 1137–1147.

16.

Dellis

Papatsoris

. Intravesical treatment of bladder pain syndrome/interstitial cystitis: From the conventional regimens to the novel botulinum toxin injections. Expert Opin Investig Drugs 2014; 23(6): 751–757.

17.

Parsons

. Successful downregulation of bladder sensory nerves with combination of heparin and alkalinized lidocaine in patients with interstitial cystitis. Urology 2005; 65(1): 45–48.

18.

Kuo

. Urodynamic results of intravesical heparin therapy for women with frequency urgency syndrome and interstitial cystitis. J Formos Med Assoc 2001; 100(5): 309–314.

19.

Parsons

Zupkas

Proctor

, et al. Alkalinized lidocaine and heparin provide immediate relief of pain and urgency in patients with interstitial cystitis. J Sex Med 2012; 9(1): 207–212.

20.

Welk

Teichman

. Dyspareunia response in patients with interstitial cystitis treated with intravesical lidocaine, bicarbonate, and heparin. Urology 2008; 71(1): 67–70.

21.

Cervigni

Natale

Nasta

, et al. Intravesical hyaluronic acid and chondroitin sulphate for bladder pain syndrome/interstitial cystitis: Long-term treatment results. Int Urogynecol J 2012; 23(9): 1187–1192.

22.

Cervigni

Sommariva

Tenaglia

, et al. A randomized, open-label, multicenter study of the efficacy and safety of intravesical hyaluronic acid and chondroitin sulfate versus dimethyl sulfoxide in women with bladder pain syndrome/interstitial cystitis. Neurourol Urodyn 2017; 36(4): 1178–1186.

23.

Arslan

Gönültaş

Gökmen

, et al. Outcomes of intravesical chondroitin-sulfate and combined hyaluronic-acid/chondroitin-sulfate therapy on female sexual function in bladder pain syndrome. Int Urogynecol J 2019; 30(11): 1857–1862.

24.

Pyo

Cho

. Systematic review and meta-analysis of intravesical hyaluronic acid and hyaluronic acid/chondroitin sulfate instillation for interstitial cystitis/painful bladder syndrome. Cell Physiol Biochem 2016; 39(4): 1618–1625.

25.

Cho

Lee

, et al. Comparison of the efficacy between transurethral coagulation and transurethral resection of hunner lesion in interstitial cystitis/bladder pain syndrome patients: A prospective randomized controlled trial. Eur Urol 2020; 77(5): 644–651.

26.

Rofiem

Hom

Fried

, et al. Use of the neodymium: YAG laser for interstitial cystitis: A prospective study. J Urol Assoc J 2009; 3(6): 473–477.

27.

Cocci

Alowidah

Skews

, et al. 421 comparison of Cystistat®, iAluril®, and Whitmore Cocktail for treatment of patients with bladder pain syndrome/interstitial cystitis. Eur Urol Suppl 2016; 15(3): e421.