On- and post-treatment symptom relief by repeated instillations of heparin and alkalized lidocaine in interstitial cystitis

Authors


Abstract

Objectives

To examine outcomes of intravesical instillations of heparin and alkalized lidocaine in patients with interstitial cystitis.

Methods

Patients with interstitial cystitis refractory to conventional therapies were given a solution of 20 000 U heparin, 5 mL 4% lidocaine and 25 mL 7% sodium bicarbonate, intravesically, weekly for 12 weeks consecutively. The treatment was regarded as “effective”, when patients rated “slightly improved” or “better” on a seven-graded scale of global response assessment. Other assessment measures included O'Leary and Sant's symptom index and problem index, visual analog scale for pain, and frequency volume chart variables.

Results

A total of 32 patients were enrolled in the study. The average age was 63.3 years. All participants had received hydrodistension 2.2 times on average, and fulfilled National Institute of Diabetes and Digestive and Kidney Diseases criteria. The therapy was effective in 60.0% of the patients at the fourth instillation, in 76.7% at the last instillation, and 90.0%, 46.7% and 16.7% at 1, 2 and 6 months after the last instillation, respectively. Most of other assessment measures improved significantly at the fourth instillation and further beyond until the end of therapy. On termination of therapy, the efficacy gradually diminished, yet mostly maintained statistical significance by 2 months post-instillation. No severe adverse events occurred.

Conclusions

A 12-week course of weekly intravesical instillations of heparin combined with alkalized lidocaine is safe and effective in relieving symptoms in interstitial cystitis patients. The effect of the treatment is maintained for 6 months. Further studies are required to optimize the number of instillations and maintenance intervals in order to maximize the therapeutic potential of simple or combined instillations in the management of interstitial cystitis.

Abbreviations & Acronyms
AVV

average voided volume

DMSO

dimethyl sulfoxide

FVC

frequency volume chart

GAG

glycosaminoglycan

GRA

global response assessment

HBS

hypersensitive bladder syndrome

IC

interstitial cystitis

NGF

nerve growth factor

NIDDK

National Institute of Diabetes and Digestive and Kidney Diseases

NSAIDs

non-steroidal anti-inflammatory drugs

NUIC

non-ulcer type IC

OSSI/OSPI

O'Leary and Sant's symptom index and problem index

UF

urinary frequency

UIC

ulcer type interstitial cystitis

VAS

visual analog scale (for pain)

Introduction

IC is characterized by a particular symptom complex with no identifiable causes.[1] The symptom complex, HBS, is defined as bladder hypersensitivity, usually associated with urinary frequency, with or without bladder pain.[2] No current treatments have a significant impact on symptoms over time, and as a result, patients are subject to numerous treatment modalities; from invasive to holistic therapies.[3-5]

One of the possible etiologies for IC is chronic and persistent deficiency of the GAG layer, which allows penetration of urine into the interstitial layer of the bladder, thereby causing inflammatory reactions.[6, 7] Heparin, a family of sulfated polysaccharide resembling GAG, is believed to bind the defect of the GAG layer on bladder surface. According to the previous reports, intravesical heparin therapy is effective in approximately half of the patients; however, it cannot produce immediate relief of IC symptoms.[7] In contrast, immediate symptom relief can be attained by intravesical lidocaine therapy. The safety and improved absorption of alkalized lidocaine was confirmed in IC patients, although the effects of alkalized lidocaine disappear within a few days.[8] Combination of heparin and alkalized lidocaine successfully attained immediate and sustained improvement; however, the patients were followed only for 2 weeks post-treatment, and backgrounds (i.e. age, sex, with or without ulcer) predictive of favorable response have not been explored.[9]

We tested the efficacy of 12-weekly intravesical instillations of a combination of heparin and alkalized lidocaine in patients with IC, and evaluated therapeutic outcomes up to 6 months after the last instillation. In addition, we examined the difference in therapeutic response according to their backgrounds.

Methods

Patients

Patients with IC refractory to conventional therapies were enrolled in the study. IC was diagnosed by three conditions: (i) lower urinary symptoms, such as urinary frequency, bladder hypersensitivity and/or bladder pain; (ii) bladder pathology proven endoscopically by Hunner's ulcer and/or mucosal bleeding after over-distension; and (iii) exclusion of confusable diseases, such as infection, malignancy or calculi of the urinary tract.[2] According to cystoscopic findings on hydrodistension, patients were categorized into two groups; UIC and NUIC. Symptoms were assessed by OSSI/OSPI. Scores six or more for both indices, despite present therapies (i.e. hydrodistension or oral drugs), were required for enrolment. At enrolment, patients' age at therapy, age at onset of IC, duration of IC symptoms, sex, number of hydrodistensions undergone before the therapy and distended bladder volume at the primary hydrodistension were recorded. Patients with an allergy to lidocaine, continuous macrohematuria, active urinary tract infection and hemorrhagic diathesis were excluded.

The protocol of the study was approved by our Institutional Review Board (#2205), and was fully explained to the patients before a written informed consent was obtained.

Therapeutic protocol

All patients were intravesically given a solution of 20 000 U heparin (Ajinomoto, Tokyo, Japan), 5 mL 4% lidocaine (Astrazeneca, Osaka, Japan) and 25 mL 7% sodium bicarbonate (Otsuka, Tokyo, Japan) weekly for 12 weeks consecutively at our outpatient clinic using an 8-Fr urethral catheter. The acidity of the solution was pH 7.5. At each treatment, patients voided before instillation, and were instructed to hold urine for 30 min after instillation. The solution was prepared under sterile conditions immediately before every instillation. Adverse events were monitored by urinalysis and interviewing patients.

Evaluation items

We used GRA as the primary outcome measure. Participants rated their symptoms on a seven-grade scale ranging from markedly worse (−3) to markedly improved (+3) compared with the baseline. Efficacy was classified as “effective” when participants reported slight (+1) to marked improvement (+3) on the GRA, otherwise efficacy was considered to be “not effective” or as “symptom recurrence” if it was during the follow-up period.[10]

Other assessments included OSSI/OSPI, VAS for pain and FVC variables. The efficacy was evaluated after the first, fourth and 12th instillations, and 1, 2 and 6 months after the last instillation. Withdrawal from the study without completing the treatment course was counted as drop-out.

Statistical analysis

Therapeutic outcomes were compared with the baseline values. For its skewed distribution, signed Wilcoxon's rank sum test for paired samples was carried out to compare the values of average voided volume, daytime urinary frequency and nocturnal urinary frequency. For other variables, Wilcoxon's signed rank test was used. Patients' background factors associated with therapeutic efficacy at the fourth instillation and 2 months post-therapy were examined by χ2-test and Fisher's exact test. P < 0.05 was considered significant. All calculations were carried out with spss, version 18.0 (SPSS, Chicago, IL, USA).

Results

A total of 32 participants (29 women and 3 men) were enrolled in the study (Table 1). The mean age was 63.3 years (range 35–82 years). All participants were compatible with the NIDDK criteria.[11] Of them, 17 were categorized as UIC, and 15 as NUIC. All patients had received hydrodistension at least once before instillation, with 2.2 times on average (range 1–7). Prior treatments included suplatast tosilate (n = 18), tricyclic antidepressant (n = 11), DMSO instillation (n = 10) and/or NSAIDs (n = 14). A total of 30 patients completed the treatment protocol and post-treatment follow up to 6 months, whereas two patients discontinued the therapy because of symptoms worsening at the fourth or sixth instillation.

Table 1. Patients' demographics
No. (male/female)32 (3/29)
Mean age (years)63.3 ± 13.8 (range 35–82)
Age at onset of IC (years)60.0 ± 14.4 (range 25–74)
Duration of IC (years)4.7 ± 3.5 (range 1–13)
Type of IC (UIC/NUIC)17/15
Past treatment 
Hydrodistension

32

2.21 times on average (range 1–7)

Distended bladder volume at primary hydrodistension (mL)570.0 ± 230.0 (range 200–1200)
DMSO instillation10
Medicine 
Suplatast tosilate18
Tricyclic antidepressant11
NSAIDs14
Others6

According to GRA, responders gradually increased with advancement of the therapy (Table 2, Fig. 1); the response rate was 33.3% after the first instillation, 60.0% after the fourth and 76.7% after the 12th, and 90.0% 1 month after the last instillation. On the termination of instillation, the rate declined to 46.7% at 2 months and 16.7% at 6 months. Post-hoc analysis indicated ulcer type IC, onset age younger than 60 years and bladder volume at primary hydrodistension less than 500 mL as prognostic factors for better therapeutic response at the fourth instillation (Table 3); however, no factors were identified for efficacy at 2 months post-therapy. Other variables showed significant improvement during the therapy (Table 4). OSPI reached a significant level of improvement as early as at the fourth instillation (P = 0.033), and it was pronounced at the 12th instillation (P < 0.001). VAS for pain showed a significant reduction after the fourth instillation from the baseline (P = 0.024) and thereafter. Average voided volume significantly increased from the fourth therapy (P = 0.029). Urinary frequency decreased significantly at the fourth therapy for daytime frequency (P = 0.003) and for night-time frequency (P = 0.001). During post-therapy follow up, all the variables showed gradual deterioration with time; however, significant improvement lasted until 2 months after the termination of instillation. There was no significant difference at 6 months after the last instillation, except for nocturnal frequency, compared with the baseline.

Figure 1.

Global response assessment for efficacy of heparin and alkalized lidocaine instillation. Patients with IC refractory to conventional therapies received a solution of 20 000 U heparin, 5 mL 4% lidocaine, and 25 mL 7% sodium bicarbonate intravesically weekly for 12 weeks consecutively. The patients were followed up at 1, 2 and 6 months post-instillation without further treatment. The efficacy was graded as “marked improved” (GRA +3), “moderately improved” (GRA +2), “slightly improved” (GRA+1), “no change” (GRA 0), “slightly worsened” (GRA −1), “moderately worsened” (GRA −2) or “marked worsened” (GRA −3). image, GRA = +3; image, GRA = +2; image, GRA = +1; image, GRA = 0; image, GRA = −1; image, GRA = −2; image, GRA = −3.

Table 2. Global therapeutic response (n = 30)
 During therapyPost-therapy
Week 1Week 4Week 121 Month2 Months6 Months
  1. †GRA: +1, +2 or +3. ‡GRA: 0, −1, −2 or −3.
Responders10182327145
Non-responders2012731625
Response rate (%)33.360.076.790.046.716.7
Table 3. Univariate analysis of overall response factors at fourth therapy and 2 months post-treatment
 Univariate analysis
Fourth therapy2 months post-treatment
ORCI (95%)P-valueORCI (95%)P-value
  1. *P-value <0.05.
Ulcer      
Ulcer/non-ulcer8.2501.154–59.0030.039*1.1670.224–6.0810.855
Sex      
Male/female4.6670.352–61.8310.2690.7500.541–1.0400.217
Age      
≥65 years/<65 years0.5000.087–2.8860.6571.2500.233–6.7150.795
Age at onset      
≥60 years/<60 years0.1210.017–0.8670.039*0.8570.164–4.4670.855
Duration of IC      
≥5 years/<5 years1.5000.266–8.4490.6851.1670.224–8.0810.855
Distended bladder volume      
≥500 mL/<500 mL0.0830.011–0.6410.023*1.2500.233–6.7150.795
Past hydrodistension      
≥2/once0.6860.119–3.9630.6732.40.444–12.9800.414
Table 4. Therapeutic effects by symptom measures (mean ± SD, n = 30)
 BaselineDuring therapyPost-therapy
Week 1Week 4Week 121 Month2 Months6 Months
  1. *P < 0.05 versus baseline, **P < 0.005 versus baseline.
OSSI13.4 ± 3.712.9 ± 3.410.9 ± 3.98.3 ± 3.6**8.8 ± 4.0**9.4 ± 4.4*9.3 ± 5.3
OSPI11.8 ± 4.211.5 ± 4.08.6 ± 4.2*6.9 ± 3.3**6.5 ± 3.6**7.0 ± 3.9**7.1 ± 4.5
VAS5.8 ± 2.75.5 ± 2.43.4 ± 2.4**3.5 ± 2.5*3.3 ± 2.3**3.8 ± 2.9*3.5 ± 2.7
AVV1 (mL)93.8 ± 65.5108.2 ± 61.6130.3 ± 61.8*143.9 ± 72.9*129.8 ± 66.4**106.1 ± 72.4118.6 ± 102.9
UF2 (day)27.1 ± 36.619.3 ± 13.4**14.4 ± 3.7**13.4 ± 4.6**14.6 ± 4.5**15.1 ± 4.2*15.0 ± 6.5
UF2 (night)4.3 ± 2.73.6 ± 2.8**2.7 ± 2.0**2.3 ± 2.4*2.3 ± 1.6**2.1 ± 1.4*2.0 ± 1.3*

As for side-effects of the therapy, no adverse events requiring additional intervention were observed. Two patients discontinued the therapy because of poor benefit. Minor side-effects included bladder pain (n = 18), gross hematuria (n = 4) and urinary tract infection (n = 3), all of which were self-limited. Gross hematuria was observed only on the day of instillation and not associated with systemic coagulation disorder (data not shown).

Additionally, 70% of patients reported slight bladder discomfort lasting for approximately 1 day every time after the administration, which also could be tolerated and decreased with continuation of the therapy. This discomfort was not related to therapeutic effect (data not shown).

Discussion

Intravesical therapy with a combination of heparin and alkalized lidocaine was first reported by Parsons.[9] The solution consisting of 40 000 U of heparin, 8 mL 2% lidocaine and 3 mL 8.4% sodium bicarbonate was given three times per week for 2 weeks. At the initial administration of the solution, 94% of patients (33 of 35 patients) reported immediate relief of both pain and urgency. However, patients were followed until 48 h after the last therapy, when 80% of them reported sustained relief of the symptoms. Another study by Welk used 10 000 U of heparin, 8 mL 2% lidocaine and 4 mL 8.4% of sodium bicarbonate for 23 female IC patients complaining of dyspareunia.[12] Patients were treated with the solution three times per week for 3 weeks. Three weeks after the therapy, 65% of patients reported a successful outcome of IC symptoms. Most of the efficacy parameters, including OSSI, OSPI, frequency, voided volume, Pelvic Pain Urgency Frequency score and Female Sexual Function Index pain domain score, showed significant improvement, supporting the effectiveness of the therapy. A double-blind, crossover, placebo-controlled trial showed that a single instillation of the solution can provide significant and immediate relief of IC symptoms up to 12 h.[13] These three studies demonstrated well the short-term efficacy, especially for pain, of intravesical therapy with a combination of heparin and alkalized lidocaine. However, they presented little data for outcomes post-administration.

Based on previous studies and the short-term efficacy of heparin instillation, we carried out the present study to assess the long-term outcomes of combined instillations, confirming the efficacy comparable with three previous studies. According to GRA, responders increased with advancement of the therapy; 33.3% after the first therapy, 60.0% at the fourth therapy and 76.7% at the 12th therapy. Once improved, there was no deterioration in efficacy during therapy. At the first week, all the parameters showed slight improvement, yet not at a significant level, whereas Parsons and Welk reported quicker responses to the therapy. The reason for the difference might be because of the difference in the study design; the previous two studies gave the solution three times per week, whereas ours was given weekly. We designed the interval according to the capacity of our outpatients' clinic and patients' convenience. However, almost all of the parameters reached a significant level of improvement at the fourth instillation. No specific backgrounds were identified as predictive factors, although patients with the ulcer type of IC, younger onset age and smaller bladder volume at primary hydrodistension were likely to be better off earlier. As these factors are related to the ulcer type of IC, the subtyping might be responsible for the responsive difference. During the post-instillation period, the response rate was maximized (90.0%) at 1 month, 46.7% at 2 months and 16.7% at 6 months; the therapeutic effect lasted an average of 4.1 months after the last therapy. Other parameters similarly showed slight deterioration. These facts suggest that repeated administration of the solution could recover the damaged GAG layer of the bladder mucosa, and that the recovery deteriorates in due time. In other words, the current therapy would not be a curative, but palliative, treatment for IC. Also suggested is the necessity for regular maintenance therapy, with 1–4 months as a possible interval.

The therapy was well tolerated. A common side-effect was bladder discomfort after instillation, which occurred to 60.0% of patients after every instillation. Two patients discontinued the therapy because of worsening symptoms, amplified with instillation. The bladder discomfort might be explained by catheterization, alkalinity of the solution, stimulation of bladder mucosa by agents and/or natural course of the disease. Though discomfort itself might not affect the therapeutic effect, it should be solved by further study. Another adverse event was gross hematuria; however, it was self-limited and observed only on the day of instillation.

The limitations of the present study should be mentioned. It was a single-armed, open-label trial with a small number of patients. The efficacy of a single agent, heparin or lidocaine, remained unevaluated; heparin instillation alone might be effective.[13] In addition, the therapeutic outcomes were assessed by subjective questionnaires, but not by objective measures, such as urine NGF level.[14] Further studies should be explored to determine: (i) composition of the solution; (ii) duration of induction therapy; (iii) interval of maintenance therapy; and (iv) therapeutic assessment by objective outcome measures.

Twelve weekly intravesical instillations of heparin combined with alkalized lidocaine safely achieved symptom relief in most IC patients, which diminished in 6 months post-treatment. Younger age and the presence of ulcers are predictive of a quicker response. Further studies are required to optimize the patient selection, the number of instillations and the maintenance interval to maximize the therapeutic potential of this therapy in controlling IC symptoms.

Conflict of interest

None declared.

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