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Keywords:

  • Interstitial cystitis;
  • l-arginine;
  • nitric oxide;
  • symptoms;
  • treatment

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Authors

Objectives To determine, in a double-blind placebo-controlled crossover study, whether l-arginine improves the symptoms of interstitial cystitis (IC), a chronic condition in which nitric oxide (NO) may be important, as previous open pilot studies suggested that l-arginine reduced the pain and frequency associated with IC.

Patients and methods Patients fulfilling the standard diagnostic criteria for IC were randomized to receive l-arginine (2.4 g/day) or placebo for one month. After a 2-week ‘washout’ period they received the other medication. Patients were assessed at each stage using a validated symptom index, a voiding diary, urine analysis and records of adverse events. Patients were asked about overall efficacy at the close of the study. The results were compared using a t-test, with significance indicated at P < 0.05.

Results Sixteen (16) patients (mean age 51.3 years) were enrolled; the mean duration of IC was 5.4 years, the IC symptom index score 29.1, their nocturnal frequency 3.5 (voided volume 182 mL) and daytime frequency 12.7 (124 mL). Patients on placebo showed no differences in any recorded variable over the baseline values. l-arginine caused a statistically significant reduction in the overall symptom score of 2.2 over baseline, but there was no difference in voided volume, frequency or nocturia. As there was no significant difference for any variable between l-arginine and placebo, this reduction in score should be regarded with caution. Three patients withdrew because of side-effects (severe headaches, night sweats and flushing).

Conclusion Oral l-arginine produces a statistically significant improvement in the IC symptom index in patients with IC, but the effect is small. This effect may not be clinically significant as there were no improvements in the other variables assessed and no significant difference between the response to l-arginine and placebo. From these results the use of l-arginine cannot be recommended for treating IC.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Authors

Interstitial cystitis (IC) is usually diagnosed when other urological causes for the characteristic irritative voiding symptoms, pain, sterile pyuria and cytologically normal urine have been excluded. IC is predominantly a disease of women [1]. The incidence of IC varies considerably between reports from European and North American series. In Europe, where rigid diagnostic criteria have traditionally been applied, the accepted incidence is 8–16 per 100 000 women [1,2]. In the USA, the reported incidence varies widely, from about double the European average [3] to nearly 100 times the average [4]. To formalize common entry criteria for IC research studies, the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases of America (NIADDK) defined specific entry criteria [5].

In addition to a widely reported variation in the incidence of IC there is also no consensus on the aetiology of this condition. Recent work has suggested that nitric oxide (NO) may play a role in the aetiology of IC [6]. NO is the oxidation product of l-arginine, a reaction catalysed by NO synthase (NOS) [7]. NO has many physiological functions but two are thought to be important in the bladder and possibly in IC. First, NO acts as a functional antagonist of smooth muscle contraction by promoting smooth muscle relaxation [8]. Second, inhibitors of NOS are associated with increased mast cell degranulation and subsequent inflammatory reactions [9,10]. Female patients with IC have significantly less NOS activity in their urine than have normal controls [6].

The administration of l-arginine experimentally to rats has been shown to increase the healing of both gastric [11] and small bowel ulcers [12]. Clinically, the administration of l-arginine has been shown to be beneficial in the protection of tissues after ischaemic injury [13], and in treating erectile dysfunction [14]. In a small, uncontrolled pilot study, l-arginine was given to a group of women with IC and a fourfold increase in the urinary NOS activity was recorded [15]. Further data from this observational study also showed an improvement in the pain and frequency of IC in patients taking 1.5 g/day of l-arginine [16]. This was confirmed by the same authors in a larger placebo-controlled trial [17] in which parallel groups of patients with IC were given either l-arginine 1.5 g/day or placebo. Ehrén et al.[18], in a small uncontrolled study, contradicted these findings; they showed no beneficial effect of l-arginine over baseline values.

Thus in the present study we determined whether there was any clear benefit from the use of l-arginine (over placebo) in treating the typical patient with IC presenting to the British urologist.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Authors

Any patient fulfilling the diagnostic criteria for IC established by the NIADDK [5] was considered for inclusion in the trial (Table 1). In addition to the exclusion criteria of the NIADDK, any patient with a history of diabetes or liver disease was excluded because of potential interactions with l-arginine [19]. All patients were initially assessed by a routine medical history and physical examination. Urine was examined microscopically and cultured for evidence of infection. Blood samples were taken to estimate renal and hepatic function. After completing a validated, self-assessment IC symptom index (ICSI) [20], they were given full information about the nature and aims of the trial, and asked to sign a consent form.

Table 1.  Criteria for selecting patients for the treatment of IC with l-arginine. Adapted from NIADDK criteria [18] and updated to include contraindications to l-arginine
Criteria Conditions
Required criteria Glomerulations (petechial haemorrhage) or Hunner’s ulcer on endoscopy and pain associated with the bladder or urinary urgency
Automatic exclusionsCapacity > 350 mL
Absence of sensory urgency with filling to 150 mL at fast fill
Involuntary bladder contractions (CMG)
Duration < 9 months
Absence of nocturia
Symptoms relieved by antibiotics, urinary antiseptics, anticholinergics or antispasmodics
Waking voiding frequency < × 8
Bacterial cystitis or prostatitis
Bladder calculi, lower ureteric calculi
Active genital herpes
Uterine, cervical, vaginal, or urethral carcinoma
Urethral diverticulum
Chemical cystitis
Tuberculous cystitis
Radiation cystitis
Benign or malignant bladder tumour
Vaginitis
Under 18 years of age
Additional exclusion criteria
 Hepatic disease
 Renal disease
 Cystic fibrosis
 Diabetes
Concurrent treatment with any of the following agentsPotassium-sparing diuretics Antibiotics
Steroids (except inhaled steroids)
H1- and H2-histamine antagonists

After a 2-week ‘run-in’ period, during which a voiding diary was completed, patients returned for review. At this stage, all eligible patients were then randomized. The subsequent treatment is summarized in Fig. 1. l-arginine was given as capsules containing 400 mg of active compound, at a total dose of 2.4 g/day; an inert placebo, in identical capsules, was also prescribed.

image

Figure 1. A summary of the double-blind placebo-controlled crossover trial format in which two groups were randomized to initially receive either l-arginine or placebo. The arrows indicate the time of assessment.

Download figure to PowerPoint

The assessment at each stage comprised an interview, the completion of voiding diaries, the ICSI and the collection of a MSU sample. At the end of the second phase, patients were seen, voiding diaries collected, the MSU sample examined, and renal and hepatic function assessed; the ICSI was recorded and the patients asked about the overall efficacy of the treatment. At each stage of the trial, both the patient and the doctors involved in the study were unaware of whether active agent or placebo was being taken.

The primary end-point of the study was a change in the ICSI score. Before recruiting the patients the study was devised to be sufficiently powered to show a 10% difference in the ICSI score. To accept that this difference was significant at P < 0.05, with 80% power, the double-blind crossover design required six patients to complete both arms of the study. The results were compared using Student’s t-test, with P < 0.05 taken to indicate significant differences.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Authors

Sixteen patients were enrolled in the trial (Table 2). All patients had normal renal and hepatic function at enrolment and this was unchanged at the end of the trial. Twelve patients completed both arms of the trial, with four withdrawing because of side-effects. Two patients withdrew because they had severe headaches; one, a 58-year-old woman, experienced severe frontal headaches on waking that began 3 days after starting the trial prescription and lasted for 7 days until she stopped taking the medication. The second patient, a 47-year-old woman, experienced morning headaches for 7 days whilst taking the trial medication, which stopped after ceasing treatment. Both patients felt that the side-effects were too severe to continue, and they were withdrawn from the study. A third patient, a 50-year-old man, stopped his medication after 24 h because he had diarrhoea and did not wish to continue the trial. A fourth withdrawal was a 58-year-old man who developed severe hesitancy during the initial 2-week run-in phase. He chose not to proceed to randomization. After the randomization code was broken at the close of the trial the three patients who withdrew through side-effects were all found to be taking placebo at the time. Three other patients, all on l-arginine, reported delayed menses, night sweats and nausea, respectively. In two other patients a UTI was diagnosed; both patients had provided sterile urine samples at the initial assessment and at the end of the 2-week run-in. During the first 4-week treatment phase both complained of increased frequency and dysuria, which was confirmed as being secondary to an infection with Escherichia coli in one and a coliform infection in the second.

Table 2.  Baseline characteristics of all patients assessed for inclusion in the trial
  Mean (range)
Characteristic Male Female Total
Number 41216
Age (years)58 (50–72)49 (26–76)51 (26–76)
Duration of symptoms (years) 3.5 (3–4) 5.9 (2–18) 5.3 (2–18)
ICSI score27 (22–32)30.4 (19–36)29.6 (19–36)
Nocturia (×/night) 4.8 (2.8–8) 3.7 (2–7.7) 4 (2–8)
Day time frequency17.6 (12–29.2)12.9 (5.1–18.8)14.1 (5.1–29.2)

In response to the overall efficacy question, ‘Did you feel that you were better taking the first or second medicine?’ three patients reported feeling better on l-arginine, one felt better on placebo and eight felt that there was no difference.

The ICSI score recorded from patients after 4 weeks of l-arginine was 7.5% lower than the mean value calculated at baseline (Table 3; P < 0.05). Although lower than the mean ICSI score on placebo, the difference was not significant (P = 0.16). Comparing the results for individual questions from the ICSI showed no significant difference between l-arginine and placebo. In response to the overall efficacy question, the three patients who felt better on l-arginine had a mean 8-point (11%) reduction in ICSI over placebo, but there were too few patients to allow a valid statistical comparison. The patient who reported feeling better after placebo than l-arginine recorded a 25% higher ICSI score on placebo than on l-arginine. There was no significant difference in either the voided volume or the daytime or nocturnal frequency between baseline and after each treatment (Table 3).

Table 3.  A summary of the measured variables at baseline and after 4 weeks of placebo or l-arginine
Mean ( e m ) variable Baseline Placebo l -arginine
  • *

    Significant difference between variable and baseline, P < 0.05.

ICSI score 29.1 (1.3) 27.8 (1.6) 26.9 (1.9)*
Nocturia (n)  3.5 (0.5)   3.6 (0.6)   3.8 (0.9)
Volume (mL)181.0 (43.2)184.0 (43.6)169.0 (35.7)
Day-time frequency (n) 12.7 (1.2) 11.7 (1.3) 12.9 (1.5)
Volume (mL)124.0 (24.1)138.0 (21.5)135.0 (26.6)

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Authors

Although there was a statistically significant improvement in the ICSI score over baseline after 4 weeks of treatment with l-arginine, the effect was not significantly better than that with placebo. In addition, l-arginine was associated with no improvement in the voided volume or frequency of micturition over baseline or placebo.

There were several side-effects during the trial period; the severe headaches occurred whilst the patients were taking placebo and thus cannot be attributed to l-arginine. The delayed menses and night sweats in two women taking l-arginine may be related to indirect hormonal effects of the agent. l-Arginine stimulates the release of prolactin from the pituitary gland [19], probably by acting on the hypothalamus. Nausea, seen in one patient taking l-arginine, has previously been reported after the intravenous administration of l-arginine [21]. Both patients with UTIs were subsequently treated with antibiotic therapy, as appropriate for the reported sensitivities. At the end of the washout phase both patients produced sterile urine samples, but during the second treatment arm a second UTI was confirmed from the MSU sample.

The rationale for administering l-arginine was that NOS activity was lower in the urine from women with IC than from controls or women with UTI [6]. The first report of the use of l-arginine to treat IC was in 1996 [15]. A group of eight women were given l-arginine (1.5–3 g/day) in an open uncontrolled study. After 1 month seven showed a symptomatic improvement, most notably in symptom score questions relating to pain. In the same report the authors noted that NOS activity in the urine was increased by the administration of l-arginine. The data from this pilot study were supported by longer term results showing that the increase in NOS activity in response to l-arginine was durable at 6 months [23]. The durability of the clinical response to l-arginine was also reported by the same group [16]; in an unblinded and uncontrolled study, l-arginine was administered to 11 patients at 1.5 g/day. After 1 month the patients reported significantly lower symptom scores related to pain than at baseline; the effect was maintained after 6 months.

The only evidence to date on the use of l-arginine in a randomized trial is from the same group [17]. Fifty-three women who satisfied the NIADDK criteria for IC were recruited across the USA after an advertisement in the Interstitial Cystitis Association newsletter. Consent and follow-up was by post or telephone, after randomization to receive either l-arginine (1.5 g/day) or placebo for up to 3 months. Analysis of all the patients randomized showed no statistical difference in the response to l-arginine or placebo. Analysing the data from patients who completed the trial (per protocol) revealed a tendency for an overall improvement in symptoms on l-arginine compared with placebo. Using a Likert scale to assess the response, l-arginine was shown to ameliorate the intensity of IC-related pain and improve the overall efficacy scores over placebo. These authors suggested that the modest placebo effect seen in their study may have been caused by the lack of contact between patient and investigator, and by the well-informed population from which the sample was drawn. The authors suggested that a crossover trial design may have been preferable.

In the only other published report of the use of l-arginine in IC, Ehrén et al.[18] conducted an open-label, unrandomized study using the ICSI of O’Leary et al.[22] and NO production as outcome measures of the efficacy of l-arginine. This group gave l-arginine to women with IC diagnosed by biopsy-confirmed evidence of bladder wall inflammation in the absence of urine infection. The NIADDK research criteria were not applied at recruitment. The first two patients in this study were given l-arginine at 3 g/day but as there was no change in symptom score the following seven patients were given 10 g/day. After 5 weeks, there was no change in the symptom score for this group either. In untreated patients with IC the urinary NO levels were significantly higher than in the patients with genuine stress incontinence who were used as controls. The level of urinary NO was unchanged by l-arginine treatment.

If the present finding that l-arginine is no more effective in the treatment of IC than placebo is to be accepted, then several potential methodological problems must be addressed, i.e. were the statistical methods sensitive enough to detect a difference, was the correct patient group recruited, and was the dose and duration reasonable? One of the advantages of a prospective double-blind crossover design is that relatively few patients are required. To avoid a Type 1 error, at an α probability of 0.05, six patients were required to complete both arms of the study; 12 patients actually completed both arms. Thus we are confident that the results should have shown a significant difference if such existed.

The NIADDK inclusion criteria applied during patient selection are well recognized and when applied strictly would include 90% of patients with a clinical diagnosis of IC. However, using these criteria may exclude patients from a trial protocol who have clinical IC but do not meet all the rigorous criteria [22]. Despite this limitation the criteria are useful, as recruitment into a clinical trial should err on the side of excluding patients with the disease rather than including those without it.

The present dose of l-arginine used was probably reasonable. In their first open-label series of patients treated with l-arginine, Smith et al.[15] administered 1.5 g/day; at this dose they showed an improvement in IC-related symptoms. The effect was confirmed at the same dose by the same group in a larger placebo-controlled study [16], although the advantage of l-arginine over placebo in this study was only marginal. However, the higher doses used by Ehrén et al.[17] produced no benefit.

The short duration of the present treatment (4 weeks) could be criticised, although Ehrén et al.[17] treated patients for 5 weeks. Wheeler et al.[23] sequentially measured urinary NOS activity, cGMP levels and nitrate-nitrite levels in eight patients given 1.5 g/day of l-arginine. At baseline, all these indices of NO function were lower in patients with IC than in control subjects, but after 2–4 weeks they increased significantly, with no further change over the following 6 months. In their open-label study with 1.5 g/day l-arginine the same group reported a symptomatic improvement in all patients after 1.1 months [15]. Thus from these data an effect of l-arginine at 2.4 g/day would be expected after 4 weeks. Moreover, in the present study, there was no difference in response to l-arginine whether it was administered before or after placebo, suggesting that there was no ‘carry over’ effect.

In conclusion, although there was an improvement in the ICSI score over baseline values when using l-arginine to treat IC, this agent did not improve measured voided volume or nocturnal and daytime frequency. The improvement associated with l-arginine was no greater than that with placebo. We cannot recommend its use in the treatment of IC.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Authors

We thank Mr I. Appleyard, Mr A.D. Joyce, Miss C. Landon, Mr S.N. Lloyd, Mr S. Prescott, Mr S.K. Sundaram, and Mr S.M. Upsdell for allowing their patients to take part in this study.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Authors
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Authors

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Authors

J.J. Cartledge, FRCS(Ed), Specialist Registrar.

A.-M. Davies, FRCS, Specialist Registrar.

I. Eardley, MA, Mchir, FRCS(Urol), FEBU, Consultant.