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May 2001; Volume 3; 33-36
By Lucretia Perilli and Vicki Ratner, MD
Little research has been conducted using alternative therapies to treat interstitial cystitis (IC). This paucity of research may be detrimental to IC patients, who inevitably seek alternative treatments on their own with virtually no medical supervision and little research-based evidence of therapeutic efficacy. The following is a review of alternative therapies used to treat IC.
The amino acid L-arginine is the only alternative therapy for IC that has been subjected to randomized, controlled trials. The basic premise for the use of L-arginine in the treatment of IC is that it helps to increase the production of nitric oxide (NO) and its precursor nitric oxide synthase (NOS). NOS and NO have antibacterial, smooth muscle relaxant, hormone-releasing, and immune-modulating effects.
Elevated NO levels typically are found in some inflammatory disorders. The first study implicating NO in IC was conducted in 1996. Researchers at Yale compared urine samples of 12 IC patients (diagnosed by NIH criteria) to those of 17 patients with a urinary tract infection and eight controls. They found that NOS production appeared to be lower than normal in IC patients (2.3 ± 1.0) and higher in UTI patients (120 ± 10) when compared with controls (14 ± 3.0).1
In a subsequent uncontrolled Yale study, researchers administered L-arginine (1.5 g/d po) for six months to 10 IC patients (diagnosed by NIH criteria). They found that L-arginine helped increase the NOS activity in the bladders of IC patients and reduced some IC symptoms, beginning at one month. All of the IC patients taking oral L-arginine for the six-month period had improvement of symptoms based on patient symptom scoring. L-arginine treatment resulted in significant decreases in urinary voiding pain (from 4.8 ± 1.3 to 0.7 ± 0.3), lower abdominal pain (from 5.0 ± 1.0 to 1.5 ± 0.6), and vaginal/urethral pain (from 4.5 ± 1.1 to 1.5 ± 0.6). Urinary frequency decreased during the day (from 13.4 ± 2.0 to 8.1 ± 1.1) and at night (from 5.3 ± 1.0 to 1.9 ± 0.6). From these results and the results of their previous study, these researchers postulated a causal link among bladder infection, inflammation, and IC.
Subsequent placebo-controlled L-arginine studies by the Yale team, however, found no significant improvement in IC symptom scores when compared with placebo. L-arginine did seem to benefit two subgroups: patients with a history of intermittent urinary tract infections and larger bladder capacities (greater than 800 cc).2-4 All of the Yale studies were funded by NIH.
Recent studies of L-arginine by other groups have not supported a benefit. A privately and institutionally funded Swedish study treated nine women with IC with 3 g/d or 10 g/d of L-arginine for five weeks. Symptoms were evaluated with an IC symptom score index, and NO production was measured. Patients with stress incontinence (n = 18) were used as controls for NO levels. NO concentration in the urinary bladder was elevated in IC patients (239 ± 60 ppb) compared with controls (15 ± 2 ppb), but L-arginine treatment did not significantly affect NO levels in IC patients (189 ± 72 ppb). Symptom scores did not change significantly with either dose of L-arginine at the five-week time point.5
A team of British researchers found similar results. In this placebo-controlled crossover study, published in 2000, 16 IC patients (diagnosed by NIH criteria) were given 2.4 g/d of L-arginine or placebo for one month. After a two-week washout period, each group received the other medication for one month. Patients in the placebo group showed no differences in any recorded variable over the baseline symptom values. L-arginine caused a statistically significant reduction in the overall symptom score from baseline, but this effect was small. Moreover, there was no significant difference in any variable between the L-arginine group and the placebo group.6
The roles of L-arginine, NO, and NOS in the etiology and treatment of IC remain controversial. Leading clinicians in the treatment of IC have largely abandoned the use of L-arginine.
Mucopolysaccharides, which include glycoproteins, glycolipids, and glycosaminoglycans, are thought to benefit IC by replacing the defective GAG lining in the bladder. Pentosan polysulfate sodium, the only oral FDA-approved treatment for IC, acts in this manner. Over-the-counter mucopolysaccharides include glucosamine, chondroitin, and aloe vera. Other herbs purported to "soothe the bladder lining" include marshmallow root (Althaea officinalis) and Spirulina species (a type of blue-green algae).
No controlled trials have been done on naturally occurring mucopolysaccharides and IC. Intravesical chondroitin has been tested in a small, open-label pilot study in which 14 IC patients (diagnosed by positive hydrodistension and positive potassium sensitivity test) were given a chondroitin compound (80 mg Urocyst-S® intravesically once weekly for four weeks, then once a month for eight to 38 weeks). Twelve patients showed positive responses, one patient failed to respond, and one relapsed at 12 weeks. The average response time was 3-12 weeks.7 Algonot®, a combination of chondroitin, glucosamine and quercetin, has been proposed as a possible treatment for IC.8
Quercetin, available in various over-the-counter (OTC) formulas, is reported to act as an antihistamine, anti-inflammatory, and antioxidant. No published, double-blind placebo-controlled studies are available. Quercetin recently has been studied as a treatment for chronic abacterial prostatitis (chronic pelvic pain syndrome in men)9 and currently is under investigation as a possible IC treatment. Most OTC formulas combine quercetin with vitamin C, which can irritate the IC bladder. An open-label study of Cysta-Q® (which does not contain added vitamin C) in 22 IC patients found that 57% of the 20 patients who completed the study showed improvement of symptoms after four weeks.10
Herbal formulas in tea and pill forms are being used to treat IC. The Chinese herbs most commonly used include gardenia (Gardenia jasminoides), licorice (Glycyrrhiza glabra), dianthus (Dianthus superbus), poria (Wolfiporia cocos), rhubarb (Rheum palmatum), rehmannia (Rehmannia glutinosa), cornus (Cornus officinalis), water plantain (Alisma plantago-aquatica), ginseng (Panax spp.), and plantain (Plantago spp.). One unpublished, open-label study that was reported in the ICA Update newsletter used a Chinese herbal formula to treat 25 women who have had IC from four to 20 years and were diagnosed by NIH criteria.11 The participants drank one cup of tea bid for six days out of every week. After three months, the dosage was reduced to one cup a day. In the first month of the study, 61% of the patients experienced a decrease of more than three points on the pain scale. Twenty-two percent had a similar response after three months. Eighteen percent did not improve. Larger, controlled studies are necessary to further evaluate these herbs.
Other Alternative Therapies
Acupuncture may be a useful complement to conventional medical care for some patients,12 but there have been no adequate clinical trials of this technique. A crossover study of 12 women with IC randomized subjects to transcutaneous electrical nerve stimulation (TENS) (applied to the posterior tibial nerve, 30 minutes qd) or acupuncture (two to three times weekly); each treatment phase lasted a month.13 Only five women completed both treatments; four dropped out after receiving acupuncture and three dropped out after receiving TENS because of lack of symptom relief. Neither treatment resulted in differences in frequency, voided volume, or visual symptom scores (analyzed by Wilcoxon signed-rank test). Only one patient experienced both subjective and objective clinically significant improvement (which lasted three months after acupuncture treatment).
Myofascial release is a type of physical therapy focused on trigger points that develop in muscles due to chronic pain or overuse.14 It is used to treat pelvic floor dysfunction, which can exist concurrently with IC.15 Anecdotally, some IC patients have benefited from this type of treatment provided by physical therapists specially trained in this technique.
MSM (methyl sulfonyl methane) is a naturally occurring organic sulfur compound that is similar chemically to the intravesical IC treatment, DMSO (dimethylsulfoxide). It is being used topically and orally by some IC patients. No clinical trials of this therapy were identified.
IC patients eagerly await more solid evidence regarding the use of alternative therapies for the treatment of their disease. One possible avenue for encouraging and expanding this area of research exists at the NIH National Center for Complementary and Alternative Medicine. As more and more IC patients turn to various alternative therapies to help with their IC symptoms, it is essential that the research community develop clinical trials utilizing standard research techniques so that unbiased, valid, peer-reviewed data will become available.
Ms. Perilli is Medical Communications Specialist at the Interstitial Cystitis Association and Associate Editor of the ICA Update. Dr. Ratner is an orthopedic surgeon, President and Founder of the ICA, and recently was appointed to the NIH Advisory Council for a four-year term.
1. Smith SD, et al. Urinary nitric oxide synthase activity and cyclic GMP levels are decreased with interstitial cystitis and increased with urinary tract infections. J Urol 1996;155:1432-1435.
2. Smith SD, et al. Improvement in interstitial cystitis symptom scores during treatment with oral L-arginine. J Urol 1997;158(3 Pt 1):703-708.
3. Wheeler MA, et al. Effect of long-term oral L-arginine on the nitric oxide synthase pathway in the urine from patients with interstitial cystitis. J Urol 1997;158: 2045-2050.
4. Korting GE, et al. A randomized double-blind trial of oral L-arginine for treatment of interstitial cystitis J Urol 1999;161:558-565.
5. Ehren I, et al. Effects of L-arginine treatment on symptoms and bladder nitric oxide levels in patients with interstitial cystitis. Urology 1998;52:1026-1029.
6. Cartledge JJ, et al. A randomized double-blind placebo-controlled crossover trial of the efficacy of L-arginine in the treatment of interstitial cystitis. BJU Int 2000;85:421-426.
7. Steinhoff G. A pilot study to determine the response of patients with IC and a positive potassium sensitivity test to intravesical chondroitin sulfate (Urocyst-S) instillation. International Bladder Symposium Poster. Washington, DC. November 4-7, 1999.
8. Theoharides TC, et al. Chondroitin sulphate inhibits connective tissue mast cells. Br J Pharmacol 2000; 131:1039-1049.
9. Shoskes DA, et al. Quercetin in men with category III chronic prostatitis: A preliminary prospective, double-blind, placebo-controlled trial. Urology 1999;54:960-963.
10. Katske F, et al. Treatment of interstitial cystitis with a quercetin supplement. Tech Urol 2001;7:44-46.
11. ICA Update. Interstitial Cystitis Association 1997;12:3.
12. Mendelowitz F, Moldwin R. Complementary approaches in the management of interstitial cystitis. In: Sant GR, ed. Interstitial Cystitis. New York: Lippincott-Raven; 1997: 235-239.
13. Geirsson G, et al. Traditional acupuncture and electrical stimulation of the posterior tibial nerve. A trial in chronic interstitial cystitis. Scand J Urol Nephrol 1993;27:67-70.
14. Bennett R. Fibromyalgia, chronic fatigue syndrome, and myofascial pain. Curr Opin Rheumatol 1998;10:95-103.
15. Zermann DH, et al. Chronic prostatitis: A myofascial pain syndrome? Infect Urol 1999;12:84-88, 92.
The editor would like to thank Robert Evans, MD, and Robert Moldwin, MD, for their valuable input in preparing the articles on interstitial cystitis contained in this issue of Alternative Therapies in Women’s Health.