Treatments/Drug Discovery

• Pudendal Nerve Stimulation Can Help when Sacral Doesn’t
  Peters KM, Killinger KA, Boguslawski BM, Boura JA. Chronic pudendal neuromodulation: Expanding available treatment options for refractory urologic symptoms. Neurourol Urodyn. 2009 Sep 28. [Epub ahead of print]
  Urologists at William Beaumont Hospital in Royal Oak, Michigan, have been trying a different approach to neurostimulation in IC and overactive bladder patients, targeting the pudendal nerve rather than one of the sacral nerves. This summary of their results in 84 patients indicates that the approach can be helpful even after the more common sacral neuromodulation stops working or doesn’t work. The approach uses a lead that is implanted near the pudendal nerve in the ischiorectal fossa, an area between the anus and “sit bones.” Sixty of the 84 patients (71 percent) had more than 50 percent improvement in symptoms, although 5 decided to have sacral neuromodulation. Nearly all (93 percent) patients who had had sacral neuromodulation fail responded to the pudendal nerve stimulation. There were seven complications requiring five revisions, and there were also four other reoperations. Five devices were taken out. The improvements in frequency, voided volume, incontinence, and urgency were significant. The abstract also noted improvement in pelvic pain. More research is needed to assess how this therapy does over the long term and to predict which patients will have success with it, noted the authors.

• Chondroitin Latches onto Damaged Bladder Lining
  Hauser PJ, Buethe DA, Califano J, Sofinowski TM, Culkin DJ, Hurst RE. Restoring Barrier Function to Acid Damaged Bladder by Intravesical Chondroitin Sulfate. J Urol. 2009 Sep 16. [Epub ahead of print]
  Chondroitin sulfate bladder instillations may work by latching on tight to damaged areas of the bladder lining, which restores the barrier function. Chondroitin sulfate instillation is in clinical trials in the United States and is approved for marketing in Canada and Europe. But how it might work is still being researched, and these urologists took a look at its actions on the microscopic level. In mouse bladder lining tissue damaged by acid, the chondroitin sulfate bound tightly—and only—to the damaged bladder surface. In addition, the chondroitin sulfate restored bladder permeability (“leakiness”) to normal. That, concluded the researchers, suggests that the glycosaminoglycan layer is a major contributor to the barrier function of the bladder lining. The dose used for instillation in humans in Canada (400 mg per instillation) is enough to achieve maximum efficacy, the authors said.

• European Association of Urology Issues Chronic Pelvic Pain Guidelines
  Fall M, Baranowski AP, Elneil S, Engeler D, Hughes J, Messelink EJ, Oberpenning F, de C Williams AC. EAU Guidelines on Chronic Pelvic Pain. Eur Urol. 2009 Aug 31. [Epub ahead of print]
  The European Association for Urology issued guidelines on diagnosis and treatment of all types of chronic pelvic pain, including chronic prostate and bladder pain syndromes, urethral pain, scrotal pain, pelvic pain in gynecologic practice, and neurogenic dysfunction. The guidelines also address the role of the pelvic floor and pudendal nerve, psychological factors, general treatment of chronic pelvic pain, nerve blocks, and neuromodulation. The journal article is a summary, but the full guidelines are available online at www.uroweb.org.

• Anesthetic Instillation Improves Pain, Frequency
  González PA, Ruiz JI, Cubillana PL, Iñiguez GD, Morcillo JC, Albacete MP. New approach in treatment of pelvic chronic pain syndrome (CPPS). [Article in Spanish] Actas Urol Esp. 2009 Jun;33(6):681-5.
  Instillation of a steroid, anesthetic, and antibiotic solution eased pain and frequency for patients at a clinic in Spain, where instillation is a new therapeutic option. Patients’ pain dropped from an average scores of 6.4 out of 10 at the start to 4.7 at one month and 2.4 at six months, with 75 percent of patients showing their pain was better. Frequency dropped from 22.5 times a day to 16.2 times at one month and 13.5 times at 6 months. Patients also rated how they were doing overall, with 30 percent saying they were much better, 30 percent moderately better, and 10 percent slightly better. (The abstract did not state how often instillations were given.)

• Botox So Far
  Rao A, Abbott J. Using botulinum toxin for pelvic indications in women. Aust N Z J Obstet Gynaecol. 2009 Aug;49(4):352-7.
  This literature review for gynecologists concludes that the conditions mostly likely to be improved by botulinum toxin (Botox) therapies are pelvic floor spasm, daily pelvic pain, and pain with intercourse. Botox also improves pain scores for provoked vestibulodynia (a type of vulvodynia), although data are limited. Randomized, controlled trials show there is a role for Botox in managing idiopathic detrusor overactivity (a type of overactive bladder), although long-term follow-up data are lacking. Potential problems with Botox injection include toxin reactions, urinary and fecal incontinence, urinary retention, and secondary treatment failure because of antibody production. The article did not discuss IC.

• Multimodal Approach Helpful, but Needs Updating
  Hanley RS, Stoffel JT, Zagha RM, Mourtzinos A, Bresette JF. Multimodal therapy for painful bladder syndrome / interstitial cystitis: pilot study combining behavioral, pharmacologic, and endoscopic therapies. Int Braz J Urol. 2009 Jul-Aug;35(4):467-74.
  Patients improved in a pilot study by some US urogynecologists of multiple therapies for IC, but the treatments were not the most modern or helpful by today’s standards. The urogynecologists used well-accepted techniques such as diet modification and timed voiding but also used daily antibiotics, Kegel exercises, and hydrodistention under anesthesia. Most IC experts today do not prescribe antibiotics unless a patient has a proven UTI. Kegel exercises are aimed at strengthening the pelvic floor muscles, but most IC expert physicians and physical therapists recognize that relaxation of the pelvic floor needs to be the aim of physical therapy at the beginning. Although hydrodistention may be helpful, many IC experts prefer other therapies first and use hydrodistention early only to make sure that other bladder conditions are not causing symptoms.

• Instilled Liposomes Beat Elmiron in First IC Patient Trial
  Chuang YC, Lee WC, Lee WC, Chiang PH. Intravesical Liposome Versus Oral Pentosan Polysulfate for Interstitial Cystitis/Painful Bladder Syndrome. J Urol. 2009 Aug 13. [Epub ahead of print]
  Liposomes beat pentosan polysulfate (Elmiron) in this first published study of liposomes instilled into the bladder in actual IC patients.  Liposomes are tiny fat-like bubbles that may coat or soothe the irritated bladder lining, and they have been researched for some time in animal models of IC.  In this small study in Taiwan, the urologists compared instillation of liposomes (80 mg/40 cc distilled water) once a week for four weeks with Elmiron (100 mg) three times a day for four weeks in 12 patients each.  The investigators evaluated how patients were doing at the beginning and at four and eight weeks after treatment started.  Frequency and nocturia went down significantly in each group, but patients who got the liposomes also had significant decreases in pain, urgency, and scores on the O’Leary-Sant symptom score.  There were no complications with the instillation.  The authors said that liposomes offered potential improvement after one course of treatment for up to eight weeks.  Large-scale, placebo-controlled studies are needed, of course, to show how well this treatment works, but it looks promising.

• Liposomes Beat DMSO, Elmiron for Easing Bladder Spasms in Animal Study
  Tyagi P, Hsieh VC, Yoshimura N, Kaufman J, Chancellor MB. Instillation of liposomes vs dimethyl sulphoxide or pentosan polysulphate for reducing bladder hyperactivity. BJU Int. 2009 Jul 7. [Epub ahead of print]
  Instilled liposomes eased bladder spasms better than DMSO or pentosan polysulfate (Elmiron) in this study of rats with irritated bladders.  Six rats each got instillations of DMSO (50 percent), Elmiron (6 mg/mL), or liposomes (2 mg/mL) for two hours.  The researchers measured the time between bladder contractions as well as bladder pressure, and the bladder pressure threshold for urination.  The time between bladder contractions increased (fewer bladder spasms) significantly after instillation with Elmiron and liposomes, but not with DMSO.  The improvement with liposomes (about 160 percent) was more than double that with Elmiron (about 60 percent). Liposomes did not affect the pressure threshold, Elmiron increased it slightly, and DMSO increased it greatly.  DMSO also increased bladder pressure, whereas liposomes and Elmiron had no effect.

• Liposomes Hold Promise for No-injection Botox Treatment
  Chuang YC, Tyagi P, Huang CC, Yoshimura N, Wu M, Kaufman J, Chancellor MB. Urodynamic and immunohistochemical evaluation of intravesical botulinum toxin A delivery using liposomes. J Urol. 2009 Aug;182(2):786-92. Epub 2009 Jun 18.
  As a treatment used in IC patients, botulinum toxin A (Botox) is usually injected into the bladder wall.  But liposomes with Botox in them may allow the medication to act where it’s needed without injection, indicates an animal study.  Rats received instillations of liposomes alone, Botox alone, and liposomes encapsulating Botox and then received a potentially irritating substance in the bladder.  The researchers measured the time between bladder contractions and also looked at molecular indicators of inflammation and nerve activity.  Although all three bladder contractions significantly, the liposomes with Botox did not compromise the animals urinary function.  They also have improvements in indicators of inflammation and nerve activity.

• Genistein, Suramin May Make IC Cells Act Normal
  Sun Y, Keay S, Lehrfeld TJ, Chai TC. Changes in Adenosine Triphosphate-stimulated ATP Release Suggest Association Between Cytokine and Purinergic Signaling in Bladder Urothelial Cells. Urology. 2009 Jul 21. [Epub ahead of print]
  Basic research related to antiproliferative factor (APF) shows that an older drug and an isoflavone found in soy have potential as effective instillations for IC.  ATP has been found to play a role in transmitting pain signals in the bladder.  Also, APF and the related epidermal growth factor (EGF) have negative effects on bladder lining cells.  This research looked at a possible relationship -- how APF and EGF affect ATP-related cell signaling. Treating normal cells with EGF or APF increased ATP release and ATP receptors, turning the normal cells into IC cells.  But when the researchers treated normal and IC bladder lining cells with genistein, which blocks EGF, release of ATP went down significantly and made IC cells act like normal ones.  Suramin treatment of normal bladder cells exposed to the destructive APF significantly reduced ATP release.  The apparent relationship between ATP-related cell signaling and cytokines should be explored further, said the investigators.

• Neurontin Helps in Severe Case, But Not by Itself
  Takatani J, Takeshima N, Okuda K, Miyakawa H, Noguchi T. A case of perineal pain related to interstitial cystitis which was supposed to be relieved with gabapentin. J Anesth. 2009;23(3):474-5. Epub 2009 Aug 14.
  Gabapentin (Neurontin) was helpful for a woman with IC and severe pain, but other treatments were needed, showed this case report by Japanese anesthesiologists.  The 60-year-old woman, who had pain in the perineal and thigh area and frequent urination, went to six different clinics over 14 months before she got her IC diagnosis.  Ineffective initial treatment included acetaminophen, a nonsteroidal anti-inflammatory drug, an SSRI antidepressant, and a muscle relaxant.  The anesthesiologists gave her epidural lumbar nerve blocks with lidocaine four times a day, which helped greatly, but low blood pressure forced the doctors to end that treatment.  She then got another nerve block in the hypogastric plexus with another medication.  She kept taking Neurontin, which helped but needed to be increased.  Ultimately, she was taking 900 mg/day.  Because it did not help her frequency, she underwent hydrodistention.  After that, her pain disappeared and her frequency returned to normal.  (The article did not specify how long.)  Neurontin was useful, but it was not the only therapy needed.

• Growth Factor Reveals Gender Differences, Points to Treatment
  Tyagi P, Tyagi V, Yoshimura N, Witteemer E, Barclay D, Loughran PA, Zamora R, Vodovotz Y. Gender-Based Reciprocal Expression of Transforming Growth Factor-Beta1 and the Inducible Nitric Oxide Synthase in a Rat Model of Cyclophosphamide-Induced Cystitis. J Inflamm (Lond). 2009 Aug 19;6(1):23. [Epub ahead of print]
  Because the cytokine transforming growth factor beta-1 (TGF-beta1) regulates nitric-oxide related inflammation, it might play a role in future IC diagnosis and treatment.  In addition, male and female bladders produce different amounts of anti-inflammatory and prohealing TGF-beta1 in response to IC-like irritation, found these researchers.  Nitric oxide (NO) is produced during inflammation and has been found in higher levels in IC patients’ urine.  Researchers found that female rats produced much higher levels of NO reaction products than male rats, even without bladder irritation.  The sexes had the same normal levels of TGF-beta1.  After bladder irritation, male rats produced much lower levels of NO reaction products and higher levels of TGF-beta1 in urine than the female rats did.  Overall, the more TGF-beta1 in the urine, the lower levels of the NO reaction products there were.  TGF-beta1 and an NO-related protein were mostly found in the bladder lining.  TGF-beta1 is known to be an anti-inflammatory and pro-healing modulator in the upper urinary tract (above the bladder), and these results imply it may also play a role like this in the lower urinary tract (bladder and below) and might lead to a helpful, healing treatment.

• Nerve Stimulation at Ankle as Good as Detrol LA for Frequency
  Peters KM, Macdiarmid SA, Wooldridge LS, Leong FC, Shobeiri SA, Rovner ES, Siegel SW, Tate SB, Jarnagin BK, Rosenblatt PL, Feagins BA. Randomized trial of percutaneous tibial nerve stimulation versus extended-release tolterodine: results from the overactive bladder innovative therapy trial. J Urol. 2009 Sep;182(3):1055-61. Epub 2009 Jul 18.
  For frequency, posterior tibial nerve stimulation (PTNS), which uses an acupuncture-like needle with electrical stimulation at the ankle, did just as well as a standard overactive bladder drug.  This trial with 100 patients with frequency pitted 12 weekly tibial nerve stimulation treatments against 12 weeks of extended-release tolterodine (Detrol LA) 4 mg/day.  When patients asked how they did overall, more who got stimulation said they were cured or improved than patients taking the drug.  Doctors treating them thought they did about the same.  The more objective measurements, such as voiding diaries and overactive bladder questionnaires, showed similar improvements in each group.  Although focused on overactive bladder treatment, this trial shows the therapy may have potential in IC.

• Nerve Stimulation at Ankle Takes Down Chronic Prostatitis Symptoms, Pain
  Kabay S, Kabay SC, Yucel M, Ozden H. Efficiency of posterior tibial nerve stimulation in category IIIB chronic prostatitis/chronic pelvic pain: a Sham-Controlled Comparative Study. Urol Int. 2009;83(1):33-8. Epub 2009 Jul 27.
  A sham-controlled study showed posterior tibial nerve stimulation (PTNS), which uses an acupuncture-like needle with electrical stimulation at the ankle, can ease symptoms and pain for men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).  Because CP/CPPS and IC are thought to have similar pain mechanisms, the technique may have potential for IC pain as well.  The study included 89 patients who had pelvic pain resistant to therapy; 45 got nerve stimulation, and 44 got sham treatment for 12 weeks.  They filled out the NIH Chronic Prostatitis Symptom Index questionnaire and rated their pain and urgency on a 10-point scale.  The investigators defined response as a drop of 50 percent or more on mean scores and partial response as a drop of 25 percent to 50 percent. At the end of treatment, pain responded to treatment in 40 percent (18 men) and partially responded in 60 percent (27), and symptoms responded to treatment in 67 percent (30) and partially responded in 33 percent (15).  Mean symptom scores dropped from 23.6 at the beginning to 10.2, pain scores from 7.6 to 4.3, and urgency scores from 5.7 to 3.4.  Scores for symptoms, urgency, and pain didn’t change at all for the men who got sham treatment.

• Visceral Pain Research Could Bring New Therapies Soon
  Sengupta JN. Visceral pain: the neurophysiological mechanism. Handb Exp Pharmacol. 2009;(194):31-74.
  Although this article mainly reviews potential mechanisms of chronic pain from internal organs, it holds out new hope for treatment.  Because reports are emerging that various peptide molecules are involved in visceral pain, better therapy to manage it may be coming “relatively soon,” said the author.

• East Asian Urologists Develop IC Guidelines
  Homma Y, Ueda T, Tomoe H, Lin AT, Kuo HC, Lee MH, Lee JG, Kim DY, Lee KS; The interstitial cystitis guideline committee. Clinical guidelines for interstitial cystitis and hypersensitive bladder syndrome. Int J Urol. 2009 Jun 22. [Epub ahead of print]
  East Asian urologists have now developed guidelines for IC diagnosis and treatment based on the Japanese guidelines, published earlier this year.  These guidelines define IC as a disease of the urinary bladder diagnosed by three requirements:
  
  
  • a characteristic complex of lower urinary tract symptoms
  • bladder pathology such as Hunner’s ulcer and bladder bleeding after hydrodistention
  • exclusion of confusable diseases

  The characteristic symptom complex, which they have termed “hypersensitive bladder syndrome” (HBS), is defined as bladder hypersensitivity, usually associated with urinary frequency, with or without bladder pain.  The authors recommend HBS as a diagnosis when that is not confirmed by the other two requirements.  Although many therapies are available, most lack a high level of evidence backing them up, leaving very few therapies to recommend.  IC has a number of causes, with interaction nervous, immune and endocrine factors forming a vicious cycle, provoking and maintaining inflammatory reactions in the bladder, said the committee.  The guidelines authors called for standardizing the criteria for including patients in clinical trials as well as for the methods for assessing treatment effectiveness to improve research for this disabling disease, which has proved to be more prevalent than previously believed.  More information about the guidelines is posted in the Clinical Care section.

• Urologic Conditions Are Undertreated
  Hall SA, Link CL, Hu JC, Eggers PW, McKinlay JB. Drug treatment of urological symptoms: estimating the magnitude of unmet need in a community-based sample. BJU Int. 2009 Jun 22. [Epub ahead of print]
  Only a small proportion of people with urologic symptoms are getting recommended drug treatments, showed an analysis of the Boston Area Community Health (BACH) Survey.  The survey included 5,503 men and women in the Boston area.  The effort assessed urologic symptoms and also medication use in the past four weeks.  Compared with the prevalence of symptoms, the prevalence of use of medications was very low among both men and women.  The highest use was in men with moderate to mild lower urinary tract and benign prostatic hyperplasia (prostate enlargement) symptoms, but even among those men, only 9.6 percent used recommended drugs.  Use of medications did not vary consistently by race and ethnicity or by socioeconomic status, but use was often related to how severe symptoms were.  Although not everyone with symptoms needs drug treatment, the results suggest there is a substantial unmet need in the general population, said the authors.

• “Love Hormone” May Soothe Sensitive Bladders
  Black LV, Ness TJ, Robbins MT. Effects of Oxytocin and Prolactin on Stress-Induced Bladder Hypersensitivity in Female Rats. J Pain. 2009 Jul 10. [Epub ahead of print]
  Oxytocin, sometimes called the “love hormone,” seems to ease bladder hypersensitivity that’s related to stress.  Because many mothers with IC have reported their bladder pain goes down during breastfeeding, the researchers tested the effects of oxytocin and prolactin, two hormones produced at that time.  Similar to humans, lactating rats are less sensitive to bladder distention than female rats who are not lactating.  Groups of female rats received either hormone or saline instilled into the lower body cavity after they were stressed with mild foot shocks.  The bladders of the rats that got oxytocin before the stressful event showed much less bladder hyperactivity in response to bladder distention than those that got prolactin or saline.  Prolactin actually made the bladder more sensitive in rats that hadn’t undergone the stress but had no effect on those that had the foot shocks.  But oxytocin eased the response to bladder distention for the rats that hadn’t been stressed.  The oxytocin-treated rats also behaved in a way that suggested they were less anxious.  Systemic oxytocin might be a worthwhile treatment for patients whose chronic pain can be exacerbated by stress.

• Biofeedback, Estim Ease Symptoms
  Bendaña EE, Belarmino JM, Dinh JH, Cook CL, Murray BP, Feustel PJ, De EJ. Efficacy of transvaginal biofeedback and electrical stimulation in women with urinary urgency and frequency and associated pelvic floor muscle spasm. Urol Nurs. 2009 May-Jun;29(3):171-6.
  Transvaginal biofeedback and electrical stimulation may cut urinary symptoms by more than half.  These nurses used the techniques in 52 women with urinary symptoms associated with pelvic floor muscle spasm.  The women reported a mean symptom improvement of 64.5 percent.

• Results of Randomized Clinical Trial of PT on the Way
  Fitzgerald MP, Anderson RU, Potts J, Payne CK, Peters KM, Clemens JQ, Kotarinos R, Fraser L, Cosby A, Fortman C, Neville C, Badillo S, Odabachian L, Sanfield A, O’Dougherty B, Halle-Podell R, Cen L, Chuai S, Landis JR, Mickelberg K, Barrell T, Kusek JW, Nyberg LM; Urological Pelvic Pain Collaborative Research Network. Randomized Multicenter Feasibility Trial of Myofascial Physical Therapy for the Treatment of Urological Chronic Pelvic Pain Syndromes. J Urol. 2009 Jun 15. [Epub ahead of print]
  This research group is putting physical therapy (PT) through rigorous testing for the urological pelvic pain syndromes, IC and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), in the last of the clinical trials through the NIH-sponsored Urological Pelvic Pain Collaborative Research Network.  The ICA covered the news about this trial in our reports from the 2008 American Urological Association (AUA) annual meeting.  Now, the AUA’s official journal, the Journal of Urology, has published the result of the preliminary study, which pitted PT for the pelvic floor against general massage.  Therapists were indeed able to adhere to a treatment protocol, essential for a valid study.  The response rate was 57 percent for the targeted PT compared with 21 percent for general massage, a significant difference.  We should be hearing about the final results of this trial at next year’s AUA meeting or possibly before then.

• New Treatments Not Ready for Prime Time, Say French Urologists
  Gamé X, Bart S, Castel-Lacanal E, De Sèze M, Karsenty G, Labat JJ, Rigaud J, Scheiber-Nogueira MC, Ruffion A; comité de neuro-urologie de l’Association française d’urologie. Alternative treatments for interstitial cystitis. Prog Urol. 2009 Jun;19(6):357-363. Epub 2009 May 5.
  After a look at various new therapies for IC, the French Association of Urology’s neurourology committee decided they’re not ready to be used routinely.  Those treatments included posterior sacral root neuromodulation, posterior tibial nerve stimulation, vanilloid agent intravesical instillation, botulinum toxin injections into the bladder muscle, and surgery.  The level of evidence so far is just too low, they said.

• Bladder Botox Gets Closer to Prime Time
  Silva CM, Cruz F. Has botulinum toxin therapy come of age: what do we know, what do we need to know, and should we use it? Curr Opin Urol. 2009 May 13. [Epub ahead of print]
  Botulinum toxin A (Botox) injection therapy for the bladder and prostate is getting closer to going prime time, although for IC, it’s still in the research arena, said these authors.  The application that has the most evidence so far is neurogenic detrusor overactivity.  This overactivity is the result of nerve or brain disease or damage, such as spinal cord injury.  For other types of bladder overactivity, prostate enlargement, or IC, they believe its use should still be restricted to research centers in well-designed clinical trials.  That Botox can be used today to avoid more invasive therapy, such as bladder augmentation surgery, for patients with hard-to-treat neurogenic bladder overactivity is a hopeful sign for people with IC.

• No Sexual Function Improvement from InterStim
  Ingber MS, Ibrahim IA, Killinger KA, Diokno AC, Peters KM. Neuromodulation and female sexual function: does treatment for refractory voiding symptoms have an added benefit? Int Urogynecol J Pelvic Floor Dysfunct. 2009 May 14. [Epub ahead of print]
  Sexual function scores didn’t improve in IC/painful bladder syndrome (PBS) patients after they got InterStim, showed this study that looked at sexual function in women who had overactive bladder or IC/PBS.  Among the 105 women they studied, the researchers had 6-month data on sexual function for 54.  Of those, only 27 were sexually active before their surgery and at the time they were followed up.  Overactive bladder patients had more of an improvement than IC/PBS patients, but neither group had a statistically significant improvement.

• Electroacupunture Eases Pelvic Pain
  Lee SH, Lee BC. Electroacupuncture relieves pain in men with chronic prostatitis/chronic pelvic pain syndrome: three-arm randomized trial. Urology. 2009 May;73(5):1036-41.
  Electroacupuncture eased symptoms and pain significantly in men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), which may mean it has potential for IC patients, too.  This Korean study was small but, nevertheless, controlled.  The 39 men were randomly assigned to three different treatments.  All got advice and were prescribed exercise.  One group received advice and exercise alone, another had that plus electroacupuncture, and another had that plus sham acupuncture.  After six weeks, symptom scores decreased significantly in the electroacupuncture group compared with the other ones, especially in pain-related symptoms.  Levels of prostaglandin E2, which plays a role in inflammation, were significantly lower in the electroacupuncture group’s urine, whereas levels rose in the other groups.

• Sleep Improves when Symptoms Do
  Nickel JC, Payne CK, Forrest J, Parsons CL, Wan GJ, Xiao X. The relationship among symptoms, sleep disturbances and quality of life in patients with interstitial cystitis. J Urol. 2009 Jun;181(6):2555-61. Epub 2009 Apr 16.
  When symptom index scores improved, so did sleep and quality of life scores, found an analysis of a trial of pentosan polysulfate (Elmiron) for IC.  The patients in the study not only completed the Interstitial Cystitis Symptom Index questionnaire but also an adapted Medical Outcomes Study Sleep scale and the Medical Outcomes Study Short Form-12 Health Survey during the trial.  By week 32 of treatment, symptom scores as well as sleep scores improved, and the degree to which sleep improved correlated with how much symptoms improved.  Those who responded to the treatment also showed significant improvement in their physical health as measured by the survey.

• New Approach Treats Hunner’s Ulcer Successfully with Steroid Injection
  Cox M, Klutke JJ, Klutke CG. Assessment of patient outcomes following submucosal injection of triamcinolone for treatment of Hunner’s ulcer subtype interstitial cystitis. Can J Urol. 2009 Apr;16(2):4536-40.
  When urologists treat IC patients’ Hunner’s ulcers directly through a cystoscope, they usually fulgurate them, that is, burn them off with electricity or a laser.  But these urologists tried a different approach, injecting a corticosteroid into the ulcer just under the mucosal layer.  With the patients under anesthesia, the doctors injected 10 mL of triamcinolone acetonide (40 mg/mL), 0.5 mL at a time, into the submucosal space at the center and periphery of 30 patients’ ulcers.  The doctors had patients answer two questionnaires, the International Prostate Symptom Score (IPSS) and the Pelvic Pain and Urgency/Frequency (PUF) symptom scale, to assess the results and also asked patients to rate their overall impression of results right after surgery.  The results were successful, with the average IPSS score dropping from 21 to 11, and the average PUF score from 20 to 11 at four weeks.  Right after the operation, 21 patients (70 percent) said they were very much improved.

• When Treatment Works, Sleep Improves
  Nickel JC, Payne CK, Forrest J, Parsons CL, Wan GJ, Xiao X. The Relationship Among Symptoms, Sleep Disturbances and Quality of Life in Patients With Interstitial Cystitis. J Urol. 2009 Apr 15. [Epub ahead of print]
  In a study of pentosan polysulfate (Elmiron), patients filled out questionnaires that allowed the researchers to see whether their sleep and quality of life improved -- in addition to their IC symptoms.  The 128 patients took 300 mg of Elmiron per day and filled out questionnaires at the start of the study and 8, 16, 24, and 32 weeks later.  The questionnaires included the Interstitial Cystitis Symptom Index, an adaptation of a standard sleep scale, and a standard 12-question health survey.  At the beginning of the study, the relationship between sleep scores and the physical and mental components of the health survey were apparent.  After 32 weeks, the 48 patients who responded to treatment had an average improvement in sleep score of about 12 points, whereas the 64 patients who didn’t respond to therapy improved by only about 2 points -- a significant difference.  Sleep improvement correlated with how much symptoms improved.  At the end of the study, the patients who did get help from the treatment had better scores on the physical component of the health survey than patients who didn’t get significant help from the treatment.

• Could Noninvasive Shock-Wave Treatment Hold Promise for IC?
  Zimmermann R, Cumpanas A, Miclea F, Janetschek G. Extracorporeal Shock Wave Therapy for the Treatment of Chronic Pelvic Pain Syndrome in Males: A Randomised, Double-Blind, Placebo-Controlled Study. Eur Urol. 2009 Mar 25. [Epub ahead of print]
  Extracorporeal shock-wave treatment (ESWT) is a noninvasive therapy that directs sound waves or “shock” waves to a problem area in the body.  It’s usually used to treat kidney stones, breaking them up into tiny fragments that can be passed in the urine.  But these urologists applied low sound waves to the perineum of men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), using no anesthesia, and got very encouraging results.  The randomized, double-blind (neither patients nor doctors knew who got the real treatment), placebo-controlled study included 60 men who had had CP/CPPS symptoms for at least three months.  The men got the real or sham treatment once a week for four weeks.  The effects on pain, quality of life, and voiding were all highly significant for the real treatment compared with the placebo.  This treatment has the advantage of being easy, safe, and relatively inexpensive, with no side effects, and it can be repeated any time.  Because CP/CPPS is similar to IC, we may hear about this treatment being tried in IC, too, in the future.

• New Instillation Combination Cuts Inflammation in the Lab
  Schulz A, Vestweber AM, Dressler D. Anti-inflammatory action of a hyaluronic acid-chondroitin sulfate preparation in an in vitro bladder model. [Article in German] Aktuelle Urol. 2009 Mar;40(2):109-12. Epub 2009 Mar 18.
  A combination of chondroitin sulfate and hyaluronic acid was studied in the laboratory for its effects on bladder lining cells.  Chondroitin sulfate, commonly used in joint supplements, is the major active ingredient of the instillation solution Uracyst (not yet approved in the United States).  Cystistat, also used for instillation, consists of a type of hyaluronic acid.  These ingredients together were added to cultures of bladder lining cells, which were then exposed to TNF-alpha to prompt inflammation.  To judge the degree of inflammation, the researchers measured levels of interleukin 6 (IL-6), a cytokine that these inflamed cells release.  After the treatment, the level of IL-6 release went down, and the treatment did not adversely affect the cells, even in high concentrations.  The researchers think this indicates that IC patients will tolerate the product well and that cell cultures are useful for screening new IC therapies.

• Urologists Give Guidance on Diagnosing, Treating IC in Kids
  Sea J, Teichman JM. Paediatric painful bladder syndrome/interstitial cystitis: diagnosis and treatment. Drugs. 2009;69(3):279-96.
  This article has done a great service by acknowledging that IC does indeed exist in children and adolescents and needs to be treated carefully.  The authors reviewed the literature on the potential causes of IC, the disease process, tests, and treatment. Most of that work has been done in adults, and only a few studies have been published -- most of them long ago -- on IC in children.  Some research indicates that about 25 percent of adults with IC had chronic urinary tract problems in childhood or IC symptoms in childhood that got more severe over time.  The authors said that, in general, the same diagnostic procedures and treatments used in adults can be used in children, with certain exceptions and, of course, adjusted medication dosages.  Those dosages are given in the article.  They noted that potassium sensitivity testing not only has limitations in adults but can be difficult to perform and even sometimes cruel in children because of the pain it may cause.  Diagnosis can be based mainly on the history and physical examinations, and voiding diaries are helpful.  In addition to common adult symptoms, especially with food and beverage triggers, children may also have wetting.
  
  Similar to that for adults, treatment for children includes managing diet triggers and using standard medicines, such as pentosan polysulfate (Elmiron), amitriptyline (Elavil), hydroxyzine (Atarax, Vistaril), cimetidine (Tagamet), or instillations.  The authors said that most physicians and parents would be reluctant to have children take amitriptyline and that low dosages may be helpful for adolescents.  For instillation, most clinicians would likely prefer “therapeutic solution” (anesthetic combinations) over DMSO, citing “transient pain” as a side effect of DMSO.  For some patients, however, the pain level may be high and the pain long lasting -- something to avoid in treating children.  The authors noted that the only report of DMSO use in children was in a four-year-old who required additional instillation with something else, which was not specified.

• Multispecialty Panel Makes IC Diagnosis, Treatment Recommendations
  Forrest JB, Mishell DR Jr. Breaking the cycle of pain in interstitial cystitis/painful bladder syndrome: toward standardization of early diagnosis and treatment: consensus panel recommendations. J Reprod Med. 2009 Jan;54(1):3-14.
  Chronic pelvic pain, often the result of IC/painful bladder syndrome (PBS), affects about 15 percent of women in the United States.  Even though IC/PBS is often the source, there are no guidelines for diagnosis and treatment, so it takes a long time for patients to get treated appropriately.  That’s why a panel of providers in urology, gynecology, urogynecology, and general women’s health met to review the recent literature, reach consensus, and develop algorithms (step-by-step recommendations) for diagnosis and treatment.  The group emphasized that diagnosis may not require every test available and can be based on a combination of things, including physical examination, questionnaires, cystoscopy, and potassium sensitivity testing.  Potassium sensitivity testing, however is painful for those with damaged bladder linings, as in IC.  The article mentions anesthetic instillation as a potential alternative.  The authors emphasized that all sources of pain should be treated and that to achieve the best outcome, providers and patients should use many treatment strategies (multimodal therapy), including oral medications, bladder instillations, dietary modification, and psychological counseling.  The primary goals are relief of pain and improvement in quality of life.  The American Urological Association is also in the process of developing guidelines.

• Pudendal Neuralgia Called Real but Rare
  Stav K, Dwyer PL, Roberts L. Pudendal neuralgia. Fact or fiction? Obstet Gynecol Surv. 2009 Mar;64(3):190-9.
  This review article takes a look at the evidence so far for pudendal neuralgia (PN) or pain along the course of the pudendal nerve.  The nerve and its branches serve the anal and genital areas.  PN is sometimes misdiagnosed as IC, unexplained vulvodynia, endometriosis, unexplained testicular pain, chronic pelvic pain syndrome, or other pelvic disorders.  Patients have often undergone many treatments that haven’t worked.  Typically, they have pain in the areas the nerve serves, which may include not only the anal and genital regions but also the inner leg, buttocks, and abdomen.  To help make the diagnosis, other conditions need to be ruled out.  Typically, the pain is worse with sitting and is relieved with standing, lying down, or sitting on a donut cushion, toilet, or other seat that takes pressure off the nerve.  Injection of nerve blocks to relieve the pain can help confirm the diagnosis.  The authors said that commonly used neurophysiologic tests are not definitive.  Treatments include avoiding the things that put pressure on the nerve and cause pain, physical therapy, pain medicines, nerve blocks, neuromodulation, or in severe cases, surgery to release the nerve.  The authors indicated that this condition shouldn’t necessarily be considered the same thing as pudendal nerve entrapment.  They concluded that the condition is rare, but since it is often mistaken for other pelvic conditions, it is hard to say how common it is.

• Botox Treatment Research Makes Progress
  Smith CP. Botulinum toxin in the treatment of OAB, BPH, and IC. Toxicon. 2009 Mar 4. [Epub ahead of print]
  Research on botulinum toxin, especially type A (Botox), is ongoing in IC, overactive bladder (OAB), and benign prostatic hyperplasia (BPH) in men.  In IC, evidence so far comes only from small series of cases. But today, for OAB and IC, treatment research is already in phase 2 and 3 clinical trials.  (Phase 3 is the final stage.) Regulators in both the United States and the European Union are evaluating the treatments.

• Botox Finding a Place in Vulvodynia, Pelvic Floor Therapy
  Abbott J. Gynecological indications for the use of botulinum toxin in women with chronic pelvic pain. Toxicon. 2009 Mar 3. [Epub ahead of print]
  Injecting botulinum toxins (usually botulinum toxin A or Botox) is being tried and studied in pelvic pain conditions that are often though of as gynecologic, most notably provoked vestibulodynia (also called vulvar vestibulitis) and pelvic floor spasm.  Patients with these conditions commonly report painful intercourse, painful bowel movements, and pain with menstrual periods.  Based on the limited literature, injecting 20 to 40 U of Botox in the vulva may help for three to six months in women with provoked vestibulodynia.  Retreatment seems to be successful and side effects limited.  Studies of Botox injection for pelvic floor muscle spasm have included more patients, and a double-blind, randomized, controlled study -- the gold standard for evaluating effectiveness -- reported significant reductions in pelvic floor pressures and some types of pain.  There was no significant difference, however, between the results of injection therapy and physical therapy.  The authors suggest that physical therapy may be appropriate as a first-line treatment, with Botox injections reserved for cases when that’s not successful.  These therapies have few side effects and look very promising, but more research needs to be done, said the authors.

• Research Group Developing Gene Therapy for IC Pain
  Goins WF, Goss JR, Chancellor MB, de Groat WC, Glorioso JC, Yoshimura N. Herpes simplex virus vector-mediated gene delivery for the treatment of lower urinary tract pain. Gene Ther. 2009 Feb 26. [Epub ahead of print]
  This abstract explains this research group’s rationale for their IC gene therapy research, which is progressing.  No matter what the cause of IC, it is painful, involving increased or abnormal pain signals.  Standard therapies are often just palliative, IC pain is hard to treat, and standard pain therapies all have drawbacks.  But this treatment the group is working on has the potential to alleviate pain effectively.  It involves using a modified simplex virus to deliver pain-killing proteins directly to the bladder.

• Receptors Are There for Potential New Cannabinoid Bladder Drugs
  Tyagi V, Philips BJ, Su R, Smaldone MC, Erickson VL, Chancellor MB, Yoshimura N, Tyagi P. Differential Expression of Functional Cannabinoid Receptors in Human Bladder Detrusor and Urothelium. J Urol. 2009 Feb 21. [Epub ahead of print]
  Researchers are already looking at cannabinoid (marijuana-related) drugs to soothe IC bladders, but until now, no one was entirely sure that the receptors were there for the drugs to act on. But this study found that the two major types of cannabinoid receptors are indeed in the bladder lining and in the bladder muscle (detrusor), with somewhat more found in the bladder lining.  That suggests, said that authors, that these receptors do play a role in the bladder and that they can serve as a target for drugs acting on symptoms of IC/painful bladder syndrome (PBS).

• Botox Injections in the Pelvic Floor Can Ease Hard-to-Treat Pelvic Pain
  Abbott J, Med Hons B. The Use of Botulinum Toxin in the Pelvic Floor for Women with Chronic Pelvic Pain-A New Answer to Old Problems? J Minim Invasive Gynecol. 2009 Jan 21. [Epub ahead of print]
  Botulinum toxin (Botox) injections into the pelvic floor as a treatment to relieve pelvic floor muscle spasm and pain is a treatment that is still in its infancy, but early research suggests it may have an important role for women whose pelvic pain doesn’t yield to currently available treatment, said these authors.  They noted that the few studies that have been done of the injections for provoked vestibulodynia (pain prompted by touch at the vaginal opening) show that these injections may be helpful in the short term -- three to six months -- and that retreatment seems to be successful, and the side effects are few.  For pelvic floor muscle pain and tenderness, there is currently only one double-blind, randomized, controlled study.  That study showed significant reduction in pelvic floor pressures with significant pain reduction for some types of pelvic pain.  Physical therapy should be used as a noninvasive, first-line treatment, with Botox injections reserved for those who are not helped.  The authors urged physicians to consider pelvic floor disorders as a cause of chronic pelvic pain in women and to diagnose and treat them as routine practice.

• Botox Injections in the Pelvic Floor Can Ease Hard-to-Treat Pelvic Pain
  Abbott J, Med Hons B. The Use of Botulinum Toxin in the Pelvic Floor for Women with Chronic Pelvic Pain-A New Answer to Old Problems? J Minim Invasive Gynecol. 2009 Jan 21. [Epub ahead of print]
  Botulinum toxin (Botox) injections into the pelvic floor as a treatment to relieve pelvic floor muscle spasm and pain is a treatment that is still in its infancy, but early research suggests it may have an important role for women whose pelvic pain doesn’t yield to currently available treatment, said these authors.  They noted that the few studies that have been done of the injections for provoked vestibulodynia (pain prompted by touch at the vaginal opening) show that these injections may be helpful in the short term -- three to six months -- and that retreatment seems to be successful, and the side effects are few.  For pelvic floor muscle pain and tenderness, there is currently only one double-blind, randomized, controlled study.  That study showed significant reduction in pelvic floor pressures with significant pain reduction for some types of pelvic pain.  Physical therapy should be used as a noninvasive, first-line treatment, with Botox injections reserved for those who are not helped.  The authors urged physicians to consider pelvic floor disorders as a cause of chronic pelvic pain in women and to diagnose and treat them as routine practice.

• Survey Shows Which Treatments Help
  Hill JR, Isom-Batz G, Panagopoulos G, Zakariasen K, Kavaler E. Patient perceived outcomes of treatments used for interstitial cystitis. Urology. 2008 Jan;71(1):62-6.
  With an internet survey, these researchers compared 750 patients’ assessments of how they fared after treatment with invasive procedures and treatment with medications.  The invasive procedures included hydrodistention (62 percent), bladder instillation (40 percent), and urethral dilatation (26 percent). Six months later, 24 to 45 percent of patients said they were improved by these procedures, whereas 27 to 50 percent felt no effect and 26 to 31 percent got worse.  The procedures with the best results for the largest share of patients were bladder instillation, which patients found to be beneficial 45 percent of the time, and sacral neuromodulation, which patients found helpful 56 percent of the time.  A small number of patients had Hunner’s lesions and underwent cauterization or removal of the lesions.  Of those, 55 percent said they were better.  For all medical therapies, more patients said they were better than worse, and most patients said medications made them perceptibly better.  Of patients who tried each medication, 53 percent said Elmiron made them feel better, 47 percent said amitriptyline (Elavil) did, 61 percent said Prelief did, 60 percent said Pyridium did, and 63 percent said codeine did.  The medications that helped least were the anticholinergic (overactive bladder) drugs, which helped from 23 to 32 percent, and diphenhydramine (Benadryl), which helped 23 percent.
  

• Advances, Setbacks Characterize Vanilloid Drug Research
  Wong GY, Gavva NR. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks. Brain Res Rev. 2008 Dec 25. [Epub ahead of print]
  The vanilloid receptor TRPV1, known popularly as the "hot pepper" receptor, is a target that researchers, including IC researchers, have long aimed at for pain reduction.  The receptor abundantly expressed in c-fibers, which are nerve fibers that sense pain.  Substances that excite the receptor, such as capsaicin and resiniferatoxin, and substances that block the receptor have both been shown to reduce pain in experimental animals.  Human trials have been done with these compounds in IC, shingles, osteoarthritis, bunionectomy, and Morton's neuroma.  Trials of resiniferatoxin for IC did not work out, but new TRPV1-related drugs, including the blockers SB-705498 and AMG 517, are being tried in other conditions, which may ultimately help in IC.  This review article summarizes the recent advances and setbacks of these compounds in drug development and predicts future directions.
  
  
• Vanilloid Receptor Plays Role in Chronic Pain and Chronic Cough
  Adcock JJ. TRPV1 receptors in sensitisation of cough and pain reflexes. Pulm Pharmacol Ther. 2008 Dec 27. [Epub ahead of print]
  The vanilloid receptor (TRPV1) may play a role in many types of pain-inflammatory, visceral, cancer, and neuropathic)-but also in inflammatory bowel disease (IBD), interstitial cystitis, urinary incontinence, pancreatitis, migraine, and airway disease (including chronic cough).   TRPV1 is a member of a distinct subgroup of the transient receptor potential (TRP) family of ion channels.  The receptor can be activated, not only by capsaicin (the hot pepper chemical) but also by other stimuli and chemicals.  Substances that mediate inflammation and have been focuses of IC research, such as adenosine triphosphate (ATP), bradykinin, nerve growth factor (NGF), and prostaglandin E2 (PGE2), may activate vanilloid receptors indirectly.  Also, after they are activated by one thing, these receptors seem to be sensitized to further activation by other things.  That may be the key to why substances that aren't normally harmful can activate this receptor and cause either pain or cough.  The receptor may be a great target, not only for pain drugs, but also for drugs to ease cough and airway problems.
  
  
• Bladder Injections of Botox Work Better than BCG
  El-Bahnasy AE, Farahat YA, El-Bendary M, Taha MR, El-Damhogy M, Mourad S. A Randomized Controlled Trial of Bacillus Calmette-Guerin and Botulinum Toxin-A for the Treatment of Refractory Interstitial Cystitis. UIJ. 2008 Dec;1(5).
  These Egyptian researchers pitted instillation of bacille Calmette-Guérin (BCG) against injections of botulinum toxin A (Botox) in a trial with 36 patients.  These patients met the old from of the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) research definition of IC, which generally includes patients with more serious disease.  One group of patients got 6 weeks of BCG therapy, the other got injections in the bladder of 300 units of Botox.  Patients filled out questionnaires and voiding diaries.  Eleven of the 16 patients who got BCG had an "excellent" overall response during the 23 weeks of follow-up, indicating a 71 percent improvement in a global rating, a 31 percent decrease in daily voids, a 54 percent decrease in nocturia, an 81 percent decrease in pelvic pain, a 71 percent decrease in urgency, and an 82 percent decrease in painful urination.  Fourteen of the 16 patients who got Botox injections had an "excellent response" over 22 weeks, indicating a 92 percent overall improvement, a 68 percent reduction in daily voids, a 100 percent improvement tin nocturia, a 96 percent decrease in pelvic pain, a 100 percent decrease in urgency, and a 92 percent decrease in painful urination.  These improvements were significantly better statistically than for patients who got BCG.  These results for BCG therapy are very different from those of a randomized, controlled NIDDK-sponsored trial in the United States, which did not find BCG instillations to be better than placebo.
  
  
• Patients Generally Satisfied with Bladder Enlargement
  Astroza Eulufi G, Velasco PA, Walton A, Guzmán KS. Enterocystoplasty for interstitial cystitis. Deferred results. [Article in Spanish] Actas Urol Esp. 2008 Nov-Dec;32(10):1019-23.
  At a hospital in Chile, 15 IC patients with very bad IC underwent bladder enlargement surgery between 1999 and 2006.  Before surgery, patients had a mean bladder capacity of 126 mL and had a mean frequency of 30.5 times a day.  After surgery, their mean bladder capacity almost tripled to 355 mL, and their mean frequency went down to 8.3 times a day.  Five patients had surgery-related complications.  Thirteen patients were satisfied with the results in terms of frequency and 11 in terms of suprapubic pain.
  
  
• Alkalinized Lidocaine Instillation Gives Sustained Relief
  Nickel JC, Moldwin R, Lee S, Davis EL, Henry RA, Wyllie MG. Intravesical alkalinized lidocaine (PSD597) offers sustained relief from symptoms of interstitial cystitis and painful bladder syndrome. BJU Int. 2008 Nov 13. [Epub ahead of print]
  Five days of instillations with a proprietary alkalinized lidocaine, PSD597, produced moderate to marked improvement in 30 percent of patients.  That compared with about 10 percent in those who got placebo in this controlled, randomized, multicenter study of 102 IC/PBS patients.  In addition the effects lasted beyond the treatment period.  The peak levels of lidocaine in the patients' bloodstream were well below the toxic level.  Although the authors called for long-term studies, they said this preliminary one showed that instillations can ease symptoms beyond the treatment period and that it is safe, well tolerated, and has none of the systemic side-effects patients often experience with oral drugs.  This study, now published in a medical journal, is one that the ICA covered in its reports from the American Urological Association Meeting last May and in the ICA Update.
  
  
• CystoProtek Supplement Helps Severe IC in Uncontrolled Test
  Theoharides TC, Kempuraj D, Vakali S, Sant GR. Treatment of refractory interstitial cystitis/painful bladder syndrome with CystoProtek-an oral multi-agent natural supplement. Can J Urol. 2008 Dec;15(6):4410-4.
  This uncontrolled study tested the IC supplement CystoProtek, which contains glucosamine, chondroitin, hyaluronate, quercetin, and rutin, in 252 IC/PBS patients (25 men and 227 women) who hadn't had success with other treatments.  The glucosamine, chondroitin, and hyaluronate are aimed at helping replace the glycosaminoglycan (GAG) layer that coats the bladder lining, and the quercetin and rutin are aimed at reducing bladder inflammation.  Patients rated their symptoms before and after treatment on a scale of 1 to 10 at various times.  Men had an average score of 7.5 at the beginning, which fell 52 percent to 3.9 after about a year, which was statistically significant.  The women were divided into two groups, those with more severe and less severe IC.  At the beginning of the study, those with more severe IC had an average score of 7.9, which fell 52 percent to 3.8 after an average of 11 months, a statistically significant difference.  Those with less severe IC had their scores fall about 44 percent from 3.2 to 1.6 after an average of 10 months, which was also statistically significant, only less so.  When the results for the women were evaluated based on the severity and length of time they had undergone treatment, the improvement was significant for the group with more severe symptoms.  The authors called for prospective, randomized trials of this and similar supplements in patients who have not had other treatments work and in patients who have not yet had any treatment.
  
  
• Botulinum Toxin Shows Potential in Chronic Pain
  Jabbari B. Botulinum neurotoxins in the treatment of refractory pain. Nat Clin Pract Neurol. 2008 Dec;4(12):676-85.
  Pain that is hard to control with most pain medications is a challenge, but one that botulinum toxins might help meet.  They have shown potential in reducing pain in IC and other conditions, and this article takes a look at why.  Animal studies show that the toxins inhibit the release of pain peptides from nerve endings and sensory nerve bundles, that the toxins have anti-inflammatory and antiglutamate effects, which may protect nerves, reduce activity of sympathetic nerves (which regulate organ function), and inhibit discharge of sensory receptors in muscle.  Long-term studies of botulinum toxin treatments in painful neck spasm (cervical dystonia) and low back pain show that the toxins' effects last after repeat injections, a sign that the treatment may help thwart the self-perpetuating nature of chronic pain.
  
  
• Oxazepam May Cut Nighttime Bathroom Trips
  Kaye M. Nocturia: a blinded, randomized, parallel placebo-controlled self-study of the effect of 5 different sedatives and analgesics. Can Urol Assoc J. 2008 Dec;2(6):604-8.
  This retired professor of medicine tested a number of medications on himself in a controlled way to see what their effects were on nighttime bathroom trips (nocturia).  The medications included the sedatives oxazepam (Serax, a benzodiazepine related to diazepam or Valium), zopiclone (Imovane, not available in the United States, related to eszopiclone or Lunesta), and trazodone (Desyrel, an antidepressant often used for sleep) and the analgesics naproxen (Naprosyn, Aleve, a nonsteroidal anti-inflammatory agent) and oxycodone (as in OxyContin and combinations).  In a previous study, he found that oxazepam decreased nocturia.  In this study, the only drugs that reduced the nocturia significantly were naproxen and oxazepam.  Oxazepam didn't change the volume of urine. Naproxen did by reducing water, salt, and potassium excretion.  Even though sleep quality improved with zopiclone and pain relief improved with oxycodone, these drugs had no effect on nocturia.  Oxazepam, he concluded, probably worked by making the bladder less irritable in a way that cannot be attributed to its sedative or pain killing effects or any decrease in urine or urine composition.  The effect might come from gamma-aminobutyric acid (GABA) effects in the spinal cord or brain.  The professor doesn't have IC, but these results might help guide research and treatment for IC patients with nocturia and sleep loss.
  
  
• Physical Therapy, Electrical Stimulation Eases Vulvodynia Pain
  Dionisi B, Anglana F, Inghirami P, Lippa P, Senatori R. Use of transcutaneous electrical stimulation and biofeedback for the treatment of vulvodynia (vulvar vestibular syndrome): result of 3 years of experience. Minerva Ginecol. 2008 Dec;60(6):485-491.
  Providers treated 145 women with vulvodynia using 10 weekly treatments of biofeedback, transcutaneous electrical nerve stimulation (TENS), and functional electrical stimulation (FES) and having the patients practice stretching exercises for the pelvic floor at home.  Vulvar pain improved for 76 percent of the women.
  
  
• Mechanisms of Chemokines in IC
  Sakthivel SK, Singh UP, Singh S, Taub DD, Novakovic KR, Lillard JW Jr. CXCL10 blockade protects mice from cyclophosphamide-induced cystitis. Immune Based Ther Vaccines. 2008 Oct 28;6(1):6. [Epub ahead of print]
  CXCR3 is a receptor for certain family of chemokines that are proinflammatory immune-system molecules.  The receptor is usually found on certain types of white blood cells involved in inflammation.  Levels of complexes with this receptor were high in IC patients' serum.  In mice with a kind of cystitis, the levels of CXCR3 chemokines and other chemokines were also high, similar to that of IC patients.  Messenger RNA for this and related chemokines were high on white blood cells in the bladder, and transcripts for other CXR3 chemokines were high in white cells in the lymph nodes in the groin.  The numbers of certain inflammatory white blood cells and mast cells were high in the spleen, bladder, and lymph nodes.  Blocking the most common chemokine that binds with CXCR3, known as CXCL10, damped down these reactions in the mice.  CXCL10 is also known to be involved in sensory nerve signaling.  This study, said the authors, is among the first to demonstrate some of the cellular and molecular mechanisms of chemokines in cystitis and may provide a new drug target for this disease.
  
  
• Gene Therapy for IC Bladder Pain Gets One Step Closer
  Yokoyama H, Sasaki K, Franks ME, Goins WF, Goss JR, Degroat WC, Glorioso J, Chancellor MB, Yoshimura N. Gene therapy for bladder overactivity and nociception with herpes simplex virus vectors expressing preproenkephalin. Hum Gene Ther. 2008 Oct 15. [Epub ahead of print]
  We reported on this University of Pittsburgh group's gene therapy work presented at the American Urological Association meeting last May.  Now, their research on potential gene therapy for IC bladder pain has been published.  They used a herpes virus vector to carry a gene for a precursor of enkephalin, one of the body's own natural opioid painkillers, into rats' bladder cells.  When the rats had bladder irritation, those who got the gene had lower bladder hyperactivity and showed less pain-related behavior than the animals that got an unrelated gene.  Laboratory analysis showed that the gene had been incorporated into the bladder and also the nerve roots that receive impulses from the bladder.  The treatment didn't affect the animals' ability to urinate normally.  This team is looking at this as a potential treatment for IC.
  
  
• Body Mechanics System Helps Ease Pelvic Pain
  Haugstad GK, Haugstad TS, Kirste UM, Leganger S, Wojniusz S, Klemmetsen I, Malt UF. Continuing improvement of chronic pelvic pain in women after short-term Mensendieck somatocognitive therapy: results of a 1-year follow-up study. Am J Obstet Gynecol. 2008 Oct 7. [Epub ahead of print]
  The Mensendieck system is a kind of physical therapy that emphasizes correcting posture, movement, and respiration patterns.  It is popular in Europe, especially in Scandinavia, where this study was done.  Forty women who had unexplained chronic pelvic pain were assigned to two groups: standard gynecologic treatment and gynecologic treatment plus Mensendieck somatocognitive therapy.  They completed questionnaires that assessed psychological distress and general well-being and rated their pain before treatment, after 90 days of treatment, and one year later.  Patients who got standard therapy did not improve significantly at one year.  By contrast, those who got the additional Mensendieck therapy had their scores improve for all motor functions and pain, as well scores for coping, and anxiety-insomnia-distress.  The investigators concluded that adding this therapy to standard care improves psychological distress, pain experience, and motor functions.  In their abstract, the authors did not state whether they evaluated patients for interstitial cystitis.
  
  
• Botox for IC Still Needs Evidence
  Apostolidis A, Dasgupta P, Denys P, Elneil S, Fowler CJ, Giannantoni A, Karsenty G, Schulte-Baukloh H, Schurch B, Wyndaele JJ. Recommendations on the Use of Botulinum Toxin in the Treatment of Lower Urinary Tract Disorders and Pelvic Floor Dysfunctions: A European Consensus Report. Eur Urol. 2008 Sep 17. [Epub ahead of print]
  This report of a European expert panel consensus conference concluded that, so far, the evidence is inconclusive for recommending botulinum toxins for IC (which they called bladder pain syndrome), prostate diseases, and pelvic floor disorders.  The panel recommended larger placebo-controlled and comparative trials to evaluate the therapies and their safety for treating lower urinary tract and pelvic floor disorders.  The evidence for use of the type A toxin (Botox) is promising, and the treatment is recommended for intractable symptoms of neurogenic detrusor overactivity, the type of bladder overactivity that can be seen in spinal cord injury or spina bifida, for example.
  
  
• Urinary Tract Destruction Calls for Cautious Use of Painkiller
  Chu PS, Ma WK, Wong SC, Chu RW, Cheng CH, Wong S, Tse JM, Lau FL, Yiu MK, Man CW. The destruction of the lower urinary tract by ketamine abuse: a new syndrome? BJU Int. 2008 Aug 1. [Epub ahead of print]
  This article by urologists in Hong Kong reports on the destructive effect of ketamine abuse on the urinary tract.  Abusers have some of the same symptoms as IC, but others as well.  Inflammation of the bladder lining, a contract bladder, frequency, and urgency were among the symptoms.  Many patients also had blood in the urine, reflux of urine from the bladder, and fluid enlargement of the kidney.  Although it doesn't address the effects of temporary, low dose, and legitimate use of this painkiller, this article does sound a note of caution on the use of this painkiller in IC patients.  The process in abusers may hold some clues to the process in IC, but the parallels emphasize how serious and physiologically destructive IC is in severe cases.
  
  
• Unmet Needs Great in Pain Management
  McCarberg BH, Nicholson BD, Todd KH, Palmer T, Penles L. The impact of pain on quality of life and the unmet needs of pain management: results from pain sufferers and physicians participating in an Internet survey. Am J Ther. 2008 Jul-Aug;15(4):312-20.
  This extensive survey and its analysis showed that, despite pain's high prevalence, many patients suffer with unrelieved or undertreated pain and that it has a huge impact on daily activities and quality of life for most sufferers.  This team surveyed both pain sufferers and physicians.  Of the 22,018 nonphysicians who responded to e-mail invitations, 606 met the survey's criteria as pain sufferers.  Of these, 359 had moderate to moderately severe chronic pain and 247 had moderate to moderately severe acute pain.  Physicians who responded included 241 specialists (orthopedic or general surgeons, pain specialists, or anesthesiologists), 125 primary care doctors, and 126 emergency medicine physicians.  Many chronic pain sufferers reported that pain had deleterious effects on their mental health, employment status, sleep, and personal relationships.  Most physicians did recognize the impact of pain on patient quality of life and that there were unmet needs in pain management, including inadequate pain control, end-of-dose pain, and side effects associated with increased dosing, which influenced their choice of pain medication.  The authors encouraged effective communication between physicians and patients to not only improve overall pain management but also to establish shared treatment goals. 
  
• Effectiveness of RTX Still Not Known
  Mourtzoukou EG, Iavazzo C, Falagas ME. Resiniferatoxin in the treatment of interstitial cystitis: a systematic review. Int Urogynecol J Pelvic Floor Dysfunct. 2008 Jun 19. [Epub ahead of print]
  Studies on resiniferatoxin (RTX) treatment for IC show conflicting results.  Of the six published studies, the largest study showed no improvement of overall symptoms after one treatment.  Smaller studies of one RTX treatment gave conflicting results.  Two studies that looked at multiple or prolonged treatment yielded more encouraging results.  The effectiveness of the therapy remains unknown.
  
  
• New Target for IC, Overactive Bladder Drug Therapy Shows Potential
  Su X, Leon LA, Wu CW, Morrow DM, Jaworski JP, Hieble JP, Lashinger ES, Jin J, Edwards RM, Laping NJ. Modulation of Bladder Function by Prostaglandin EP3 Receptors In the Central Nervous System. Am J Physiol Renal Physiol. 2008 Jul 16. [Epub ahead of print]
  Researchers at GlaxoSmithKline are focusing on another receptor that may be a target for overactive bladder or IC drugs, the prostaglandin EP3 receptor in the central nervous system.  These receptors, when triggered, may excite bladder activity.  They administered two EP3 blockers, called DG041 and CM9, in both the abdominal cavity and the brain in experimental animals to assess the reaction of the bladder to being distended.  Both compounds showed high affinity for the receptors, and both blocked the cellular activity induced by a compound that excites that receptor.  The compounds administered both ways reduced the frequency of bladder contractions but not their strength, but administering the compounds in the body cavity produced strong, long-lasting effects, whereas administration in the brain produced only transient effects. That means, said the investigators, that these EP3 receptors are involved in urination at spinal and supraspinal centers and in sensation of bladder pain at the spinal cord level.  Some EP3 receptor blocker may help control bladder overactivity and pain, they concluded.
  
  
• Researchers Look at Drug Target for Pain Hypersensitivity, Bladder Pain
  Robbins MT, Ness TJ. Footshock-Induced Urinary Bladder Hypersensitivity: Role of Spinal Corticotropin-Releasing Factor Receptors. J Pain. 2008 Jul 15. [Epub ahead of print]
  Receptors for corticotropin-releasing factor (CRF) might be a good target for drugs to ease bladder pain.  Because hypersensitivity to pain is thought to play a role in bladder pain and because it is known to be brought on by stress, the investigators looked at ways to block that response in stressed rats.  When stressed (by footshock), the rats’ bladders became hypersensitive.  The researchers found that blocking the CRF(2) receptor, but not the CRF (1) receptor calmed the response to bladder distention.  They administered a CRF(2)-like compound, urocortin 2, to the spine, which increased the response in a way that was similar to stress.  The effect was significantly calmed by pretreating the animals with spinal aSVG30, a CRF(2) receptor blocker.  Neither CRF nor the CRF(1) receptor blocker antalarmin had any effect on the bladder responses.  The study supports the role of stress in making bladder pain worse and also implicates spinal urocortins and their receptor, CRF(2), as players in this process.  This could ultimately lead to more effective treatments for IC pain as well as chronic pain that is worsened by stress, said the investigators.
  
  
• ATP Receptor Is Also Target for Bladder Pain Drug Development
  Brederson JD, Jarvis MF. Homomeric and heteromeric P2X3 receptors in peripheral sensory neurons. Curr Opin Investig Drugs. 2008 Jul;9(7):716-25.
  These neuroscience researchers at Abbott Laboratories detail what is known about the receptors for ATP and their role in pain, especially bladder pain.  One of them, the P2X3 receptor, is very common in the bladder, which is rich in neurons containing this receptor.  When ATP or similar compounds attach to the receptor, nerves are more sensitive to noxious stimulation.  In animal research, blocking this receptor fully blocked certain types of chronic inflammatory and neuropathic pain.  This receptor will be an important target for drugs for chronic pain including bladder pain.
  
  
• Osteopathic Technique Eases Pelvic Pain
  Grimaldi M. Painful perineum in all its forms. Contribution of manual medicine and osteopathy. Clinical study. [Article in French] J Gynecol Obstet Biol Reprod (Paris). 2008 Jul 7. [Epub ahead of print]
  This osteopathic gynecologist and colleagues used “manual medicine” to help treat pelvic pain, such as painful intercourse, vulvodynia, and coccygodynia, which, the author said, can be brought on by a bone and myofascial disorder.  Six patients at this center and 86 others at other centers worldwide were treated, with 71 having satisfactory results after two sessions.  The encouraging results to be confirmed on a larger scale to establish an appropriate teaching protocol, noted the author.
  
  
• When Elmiron Controls Symptoms, Patients Are Satisfied with Treatment
  Sand PK, Kaufman DM, Evans RJ, Zhang HF, Fisher DL, Nickel JC. Association between response to pentosan polysulfate sodium therapy for interstitial cystitis and patient questionnaire-based treatment satisfaction. Curr Med Res Opin. 2008 Jun 25. [Epub ahead of print]
  This study showed that patients who got good symptom control (a reduction of 30 percent or more) with pentosan polysulfate (Elmiron) were more satisfied with their treatment.
  
  
• Newly Discovered Receptor Shows Potential as Bladder Pain Target
  Lashinger ES, Steiginga MS, Hieble JP, Leon LA, Gardner SD, Nagilla R, Davenport EA, Hoffman BE, Laping NJ, Su X. AMTB, a TRPM8 Channel Blocker: Evidence in Rats for Activity in Overactive Bladder and Painful Bladder Syndrome. Am J Physiol Renal Physiol. 2008 Jun 18. [Epub ahead of print]
  Earlier this year, Japanese researchers discovered that a single receptor TRPM8, is likely responsible for all cold sensation.  That shows potential for activating the pain reducing properties of cold and also blocking pain sensations (which can be like those resulting from extreme cold).  Now, investigators at GlaxoSmithKline are studying the receptor’s potential as a drug target for overactive bladder and bladder pain.  They used a blocker, known as AMTB, of the TRPM8 channel to see if it changed the animals’ reactions to bladder filling and found that it did reduce both voiding reflexes and pain reflexes.
  
  
• Drug Therapy for Chronic Pain Outlined
  Lynch ME. The pharmacotherapy of chronic pain. Rheum Dis Clin North Am. 2008 May;34(2):369-85.
  In this article, these Canadian pain management specialists outline what they believe the best evidence supports as the approach to chronic pain.  (This is aimed mainly at rheumatic diseases, which include fibromyalgia.)  The usual approach is to start with a nonopioid painkiller for mild to moderate pain.  If this is inadequate or patients don't tolerate it well and if sleep loss is also a concern, then it is reasonable to add an antidepressant with painkilling qualities.  If there is a component of nerve pain or fibromyalgia, then they suggest trying one of the gabapentinoids, such as gabapentin (Neurontin) or pregabalin (Lyrica).  When that approach is inadequate, then they suggest adding an opioid analgesic.  But for moderate to severe pain, they would start a trial of a chronic opioid earlier.  Cannabinoids and topicals may also be appropriate as single agents or in combination, they said.
  
  
• GAG Replacer Instillation Helps Increase Bladder Capacity
  Daha LK, Riedl CR, Lazar D, Simak R, Pfluger H. Effect of intravesical glycosaminoglycan substitution therapy on bladder pain syndrome/interstitial cystitis, bladder capacity and potassium sensitivity. Scand J Urol Nephrol. 2008 Jan 8:1-4. [Epub ahead of print]
  At this Austrian clinic, urologists gave 27 patients GAG-replacing instillations weekly for 10 weeks.  They used a modified potassium sensitivity test after instillation of the therapy to help assess response.  In the 13 patients who did respond, maximum bladder capacity doubled with potassium instillation compared with their previous response to it.  Their capacity in response to saline instillation increased 17 percent.  The others had their capacity decrease by 35 percent with a saline solution and experienced no change in response to the potassium solution.
  
  
• Drug Development Programs Take Aim at “Hot Pepper” Receptor
  Messeguer A, Planells-Cases R, Ferrer-Montiel A. Physiology and pharmacology of the vanilloid receptor. Curr Neuropharmacol. 2006 Jan;4(1):1-15.
  This article reviews research on vanilloid receptor 1, the “hot pepper receptor,” and discusses the great potential for drugs that target it.  Interestingly, this receptor is made very active by inflammatory agents, which is thought to be part of the process of sensitizing pain receptors leading to oversensitivity to heat.  The research is building a strong case that this receptor is involved in both outer-body and internal organ inflammatory pain, such as inflammatory bowel disease, bladder inflammation, and cancer pain.  Drug development programs aimed at this receptor are intensive.  The challenge will be to develop receptor blockers that correct overactivity while still allowing normal pain and sensation, said the authors.  

Revised October 27, 2009