Inflammatory Response Linked to IC
Schrepf A, O’Donnell M, Luo Y, Bradley CS, Kreder K, Lutgendorf S. Inflammation and inflammatory control in interstitial cystitis/bladder pain syndrome: Associations with painful symptoms. Pain. 2014 Jun 5. pii: S0304-3959(14)00262-0. doi: 10.1016/j.pain.2014.05.029. [Epub ahead of print]
Researchers from the University of Iowa found higher levels of toll-like receptors (TLR), especially TLR-4, and other markers of inflammation among women with IC, suggesting that an inflammatory response may play a role in IC. The study was part of the Multidisciplinary Approach to Pelvic Pain (MAPP) study, and involved 51 IC patients and 28 healthy controls. TLR are proteins involved in the body’s immune response, and according to this research, TLR-4 appears to play a key role in painful IC symptoms.
NGF Level Reflects Severity of IC Symptoms
Kim SW, Im YJ, Choi HC, Kang HJ, Kim JY, Kim H. Urinary nerve growth factor correlates with the severity of urgency and pain. Int Urogynecol J. 2014 May 28. [Epub ahead of print]
Results of a study of potential IC biomarkers revealed that levels of urinary nerve growth factor (NGF) are directly related to the severity of urinary urgency among IC and OAB patients, and pain among IC patients. The South Korean study was conducted with 83 patients with lower urinary tract symptoms including those with OAB and IC, and a control group of 24 patients with stress urinary incontinence or microscopic hematuria. Levels of NGF and Prostaglandin E2 were assessed, but only NGF had a significant correlation with symptom severity, and only among those with OAB and IC for urgency and those with IC for pain.
IC Increases Risk of Heart Disease
Chen HM, Lin CC, Kang CS, Lee CT, Lin HC, Chung SD. Bladder pain syndrome/interstitial cystitis increases the risk of coronary heart disease. Neurourol Urodyn. 2014 Jun;33(5):511-5. doi: 10.1002/nau.22444. Epub 2013 Jun 27.
A study of 752 IC patients and 3,760 controls revealed a higher incidence of coronary heart disease (CHD) among those with IC. The study subjects were participants in the Taiwan Longitudinal Health Insurance Database 2000. Researchers tracked each individual for 3 years and found that CHD occurred more than twice as often among IC patients (19.5 vs. 8.87 cases per 1,000 person years for IC vs. control, respectively). The study authors recommend that clinicians evaluate IC patients for CHD risk factors.
Vulvodynia Remission More Likely in Secondary Disease
Nguyen RH, Mathur C, Wynings EM, Williams DA, Harlow BL. Remission of vulvar pain among women with primary vulvodynia. J Low Genit Tract Dis. 2014 May 22. [Epub ahead of print]
Women who have primary vulvodynia (pain begins upon first tampon insertion or intercourse) are 43% less likely to experience remission from pain than women who have secondary vulvodynia (pain begins after a period of pain-free intercourse). This research suggests that different mechanisms may underlie each type of vulvodynia.
Oxidative Stress May Have Role in IC
When Japanese researchers induced IC in rats using hydrogen peroxide (H2O2), they found the same changes in mRNA expressions of TRP channels as seen in the bladder mucosa patients with IC. These changes were not observed in the saline control group. H2O2 is known to cause oxidative stress and inflammation in the mouse bladder; the similarities in the bladder mucosa of rats and humans with IC suggest that oxidative stress may be a factor in IC development.
AUA session: Urodynamics/Incontinence/Female Urology: Basic Research II
Title: Voiding behavior and transient receptor potential (TRP) channel expressions in a novel rate model of cystitis induced by hydrogen peroxide (H2O2)
Publication Number: MP4-07
Authors: Rino Sugiyama*, Naoki Aizawa, Hiroki Ito, Yukio Homma, Yasuhiko Igawa, Tokyo, Japan
Inflammation May Play a Role in Development of IC/CP Co-morbid Pain Conditions
Researchers found differences in inflammatory responses among people with IC and chronic prostatitis (CP) who did and did not have co-morbid pain conditions. Using data from patients enrolled in the Multidisciplinary Approach to Pelvic Pain (MAPP) study, researchers found higher plasma IL-6 levels and greater cytokine response to TLR4 stimulation among IC/CP patients who also had IBS, vulvodynia, chronic fatigue syndrome, temporomandibular joint disorder, and fibromyalgia.
AUA Session: Infections/Inflammation of the Genitourinary Tract: Interstitial Cystitis
Title: Inflammatory biomarkers are associated with co-morbid pain conditions in UCPPS patients: a MAPP study
Publication Number: PD9-03
Authors: Catherine Bradley*, Andrew Schrepf, Susan Lutgendorf, Michael O'Donnell, Yi Luo, Karl Kreder, Iowa City, IA
Genes Might Give Clues to IC Pathology
Colaco M, Koslov DS, Keys T, Evans RJ, Badlani GH, Andersson KE, Walker SJ. Correlation of Gene Expression with Bladder Capacity in Interstitial Cystitis/Bladder Pain Syndrome. J Urol. 2014 May 16. pii: S0022-5347(14)03576-9. doi: 10.1016/j.juro.2014.05.047. [Epub ahead of print]
Researchers found variations in gene expressions among women with different types of IC, which may provide insight into potential causes of the disease. Microarray analysis of bladder biopsies from 16 women with and without IC showed genetic differences among women with IC who had low vs. normal bladder capacity; there were no significant differences among IC patients and controls with normal bladder capacity. The pathways related to inflammatory and immune responses were most involved.
Stress Response Implicated in IC and Other Related Disorders
Martínez-Martínez LA, Mora T, Vargas A, Fuentes-Iniestra M, Martínez-Lavín M. Sympathetic nervous system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: a review of case-control studies. J Clin Rheumatol. 2014 Apr;20(3):146-50. doi: 10.1097/RHU.0000000000000089.
A literature review suggests that the body’s stress response may be involved in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and IC. The review included 196 studies, of which 65% showed a sympathetic nervous system response. The authors say these findings raise the possibility that sympathetic dysfunction could be a common underlying pathogenesis in these conditions, which may have clinical implications for treatment.
Vulvodynia and Orofacial Pain: Link Suggests Common Etiology
Bair E1, Simmons E, Hartung J, Desia K, Maixner W, Zolnoun D. Natural History of Comorbid Orofacial Pain Among Women with Vestibulodynia. Clin J Pain. 2014 Feb 21. [Epub ahead of print]
A survey taken by a group of women with vulvodynia showed that 66% of them also experienced orofacial pain (OFP), which is felt in the face or mouth. The 71 women in this study were originally part of a group of 138 patients who answered questionnaires about demographics, pain, anxiety, somatic (body) awareness, and symptoms of OFP; this study group agreed to retake the same questionnaires after a 2-year follow up period. With so many patients experiencing OFP, this research suggests the possibility that these conditions share an underlying cause.
IC Study Shows Link Between Inflammation, Nerve Fibers, and Symptoms
Liu BL, Yang F, Zhan HL, Feng ZY, Zhang ZG, Li WB, Zhou XF. Increased Severity of Inflammation Correlates with Elevated Expression of TRPV1 Nerve Fibers and Nerve Growth Factor on Interstitial Cystitis/Bladder Pain Syndrome. Urol Int. 2014 Jan 23. [Epub ahead of print]
In a study of the role of inflammation in IC, researchers found that bladder inflammation and symptoms were linked to an increased presence of immunoreactive nerve fibers and nerve growth factor. They tested bladder biopsies from 53 IC patients and 27 controls for the presence of inflammation, TRPV-1 and PGP9.5-immunoreactive nerve fibers, and nerve growth factor. All three were associated with severity of inflammation; TRPV-1 was also linked to pain and urgency scores.
Could Vulvodynia Be Identified Earlier? Risk Factors Give Clues
Reed BD, Legocki LJ, Plegue MA, Sen A, Haefner HK, Harlow SK. Factors associated with vulvodynia incidence. Obstet Gynecol. 2014 Feb;123(2 Pt 1):225-31. doi: 10.1097/AOG.0000000000000066.
By screening a group of women who did not have vulvodynia every six months for 2.5 years, researchers at the University of Michigan identified several factors associated with later development of the disease. Those factors were: being young, Hispanic, married or living as married, and having or having had vulvar pain (but not meeting vulvodynia criteria), as well as sleep disturbances, chronic pain in general, specific comorbid pain disorders, and specific comorbid psychological disorders. These findings suggest that we might be able to identify the onset of the disease in an earlier phase of its development.
Cesarean Section Linked to CPP
Li WY, Liabsuetrakul T, Stray-Pedersen B, Li YJ, Guo LJ, Qin WZ. The effects of mode of delivery and time since birth on chronic pelvic pain and health-related quality of life. Int J Gynaecol Obstet. 2014 Feb;124(2):139-42. doi: 10.1016/j.ijgo.2013.07.029. Epub 2013 Oct 17.
A look at the effect of childbirth on the development of chronic pelvic pain (CPP) among first-time mothers showed that CPP was more prevalent among those who had a cesarean section, and that the rate of CPP increased the longer it had been since they gave birth. Among the 1456 Chinese women in the study, CPP occurred in 11.2% of those who had a cesarean section vs. 6.9% of those with a vaginal delivery. In terms of time since birth, CPP occurred among 2.3% at less than 1 year, 9.3% at 1-5 years, 10.7% at 6-10 years, and 13.1% at more than 10 years. Cesarean section, longer time since birth, and CPP were all associated with a lower health-related quality of life score.
Dysmenorrhea May Play a Role in Noncyclic Chronic Pelvic Pain
Westling AM, Tu FF, Griffith JW, Hellman KM. The association of dysmenorrhea with noncyclic pelvic pain accounting for psychological factors. Am J Obstet Gynecol. 2013 Nov;209(5):422.e1-422.e10. doi: 10.1016/j.ajog.2013.08.020. Epub 2013 Aug 22.
Researchers from NorthShore University HealthSystem in Illinois found that the incidence of noncyclic (not related to menstruation) chronic pelvic pain is significantly higher among women who have dysmenorrhea (severe menstrual pain) than among those who do not. For the study, which looked at the frequency of menstrual, somatosensory, and psychological risk factors between women with and without dysmenorrhea, 1,012 women of reproductive age completed a 112-item questionnaire about mood, fatigue, physical activity, somatic (physical) complaint, and pain. The results showed that 13% of the women who had severe menstrual pain also had noncyclic pelvic pain, compared to 1% of women without dysmenorrhea. The research was able to predict 90% of cases of noncyclic pelvic pain based on the presence of dysmenorrhea, somatic complaint, and low ability for physical activity. Further research is needed to determine whether dysmenorrhea is a cause of noncyclic pelvic pain or shares underlying neural mechanisms.
Pain Response is Different in Women with IC
Ness TJ, Lloyd LK, Fillingim RB. An Endogenous Pain Control System Is Altered In Subjects With Interstitial Cystitis. J Urol. 2013 Aug 20. pii: S0022-5347(13)05144-6. doi: 10.1016/j.juro.2013.08.024. [Epub ahead of print]
Researchers from the University of Alabama have found that conditioned pain modulation (CPM), a phenomenon in which pain in one part of the body inhibits pain in other parts of the body, is altered in women with IC. Studies of other chronic pain conditions—such as fibromyalgia and irritable bowel syndrome—have shown a similar change in the body’s pain response. For this study, pain tolerance in women with and without IC was assessed by immersing one hand in ice water and then measuring their pain tolerance when heat was applied to the lower extremity on the opposite side. Women without IC had significant increases in their tolerance of heat pain, while women with IC had significant decreases in pain tolerance. This change in the body’s pain inhibitory system among those with IC (and other chronic pain conditions) suggests that a deficit in the natural pain inhibitory system may contribute to the disorder.
Vulvodynia Often Co-Exists with IBS and Fibromyalgia
Nguyen RH, Veasley C, Smolenski D. Latent class analysis of comorbidity patterns among women with generalized and localized vulvodynia: preliminary findings. J Pain Res. 2013 Apr 18;6:303-9. doi: 10.2147/JPR.S42940. Print 2013.
In a study of 1,457 women with vulvodynia, researchers at the University of Minnesota School of Public Health found that more than half reported having at least two other conditions, with fibromyalgia and irritable bowel syndrome (IBS) being the most common. These findings may help provide insight into potential shared mechanisms involved in these three conditions.
BPS and Endometriosis Often Occur Together
Tirlapur SA, Kuhrt K, Chaliha C, Ball E, Meads C, Khan KS. The 'evil twin syndrome' in chronic pelvic pain: A systematic review of prevalence studies of bladder pain syndrome and endometriosis. Int J Surg. 2013 Feb 15. pii: S1743-9191(13)00034-4. doi: 10.1016/j.ijsu.2013.02.003. [Epub ahead of print]
In this British study, researchers searched medical databases to determine the prevalence of bladder pain syndrome (BPS) alone and the co-existence of BPS and endometriosis—nicknamed ‘evil twin syndrome’—among women with chronic pelvic pain (CPP). Their search led to nine studies that included a total of 1016 women with CPP. The mean prevalence of BPS, endometriosis, and co-existing BPS and endometriosis was 61 percent, 70 percent, and 48 percent, respectively. The researchers concluded that BPS often co-exists with endometriosis and that clinicians need to actively look for it in women with CPP.
Imaging Shows Brain Differences in Men with CPP
Mordasini L, Weisstanner C, Rummel C, Thalmann GN, Verma RK, Wiest R, Kessler TM. Chronic pelvic pain syndrome in men is associated with reduction of relative gray matter volume in the anterior cingulate cortex compared to healthy controls. J Urol. 2012 Dec;188(6):2233-7. doi: 10.1016/j.juro.2012.08.043. Epub 2012 Oct 22.
To assess central nervous system involvement in chronic pelvic pain (CPP), Swiss researchers at the University of Bern compared the brain MRIs of 20 men with refractory CPP and 20 healthy, age-matched men. They found that the men with CPP had less gray matter volume in the anterior cingulate cortex, the part of the brain involved in processing emotional pain. These findings suggest a role for the central nervous system in CPP, and may explain why these men have not responded to treatments targeted to peripheral symptoms.
IC Linked to Arthritis
Keller JJ, Liu SP, Lin HC. A case-control study on the association between rheumatoid arthritis and bladder pain syndrome/interstitial cystitis. Neurourol Urodyn. 2012 Nov 5. doi: 10.1002/nau.22348. [Epub ahead of print]
Using insurance claims data from patients in Taiwan, researchers found a higher incidence of IC in people who had been previously diagnosed with rheumatoid arthritis (RA). The study included data on 9,269 people with IC and 46,345 randomly selected controls. Just over 2 percent of those with IC had RA, compared with about 1 percent of the controls; the odds ratio for prior RA among cases was calculated to be 1.66. After adjusting for socio-demographic factors and co-existing medical conditions, the researchers concluded that there is an association between RA and IC.
Could Pelvic Surgery be Related to Onset of IC?
Warren JW, Howard FM, Morozov VV. Is there a high incidence of hysterectomy and other nonbladder surgeries before and after onset of interstitial cystitis/bladder pain syndrome? Am J Obstet Gynecol. 2012 Oct 15. pii: S0002-9378(12)01080-0. doi: 10.1016/j.ajog.2012.10.008. [Epub ahead of print]
Compared to controls, the people with IC in this study were about 15 times more likely to have had non-bladder pelvic surgery the month before their IC diagnosis, and about 25 times more likely to have had a hysterectomy. The study used the database from a retrospective case-control study of 312 IC cases and matched controls, plus a longitudinal study of those cases that examined the lifetime approximated annual incidence of surgeries and the incidence in the months before and after the onset of IC. The authors conclude that there may be a very high incidence of non-bladder surgeries just before the onset of IC.
Researchers Build a Case for Urinary Stone-IC Link
Keller J, Chen YK, Lin HC. Association of bladder pain syndrome/interstitial cystitis with urinary calculus: a nationwide population-based study. Int Urogynecol J. 2012 Aug 16. [Epub ahead of print]
A population-based study in Taiwan suggests an association between urinary calculus (UC), or stones, and the later development of BPS/IC. Conditional logistic regression analysis of 9,269 patients with IC and 46,345 controls showed that 8.1 percent of those with IC had UC in the past, compared to only 4.3 percent of the control group. The association was significant regardless of the location of the stone—whether in the kidney, ureter, bladder, or an unspecified location—and the researchers adjusted the data for chronic pelvic pain, IBS, fibromyalgia, chronic fatigue syndrome, depression, panic disorder, migraine, sicca syndrome, allergy, endometriosis, and asthma. One past study had suggested an association between UC and IC, but this was the first population-based study to investigate this link.
CPPS Pain More Intense During Winter
Hedelin H, Jonsson K, Lundh D. Pain associated with the chronic pelvic pain syndrome is strongly related to the ambient temperature. Scand J Urol Nephrol. 2012 Mar 27. [Epub ahead of print]
In a questionnaire-based study of 31 Scandinavian men with chronic pelvic pain syndrome (CPPS), Swedish researchers found that these men experienced three times more intense pain during winter months than in warmer seasons. The men ranged in age from 35-66 and had had CPPS for 3-42 years. The study used the National Institutes of Health Chronic Prostatitis Symptom Index questionnaire and included questions about symptom intensity during the different seasons. All participants reported a worsening of their condition as the weather became colder. More research is needed to understand the link between weather and pain.
An Unusual Case Shows Importance of Medical Detective Work
Thomas JS, Crew J. Obstructing urethral calculus in a woman revealed to be the cause of chronic pelvic pain. Int Urogynecol J. 2012 Mar 10. [Epub ahead of print]
Although stones in the urethra (urethral calculi) are extremely rare in Caucasian women, that’s just what turned out to be the cause of one woman’s chronic pelvic pain, as described in this article. At age 51, this patient was diagnosed with chronic pelvic pain in the vagina following a primary posterior vaginal wall repair. Four years later, she sought medical help for urinary retention, which was caused by a stone that had moved down into her urethra. After being treated for the obstruction, her chronic pelvic pain completely disappeared. Given the fact that this patient’s vaginal pain was caused by a problem elsewhere in the pelvis, the authors of this case study emphasize the importance of investigating all potential sources of chronic pelvic pain, even for highly localized pain.
Changes in the Brain Linked to CPP
As-Sanie S, Harris RE, Napadow V, Kim J, Neshewat G, Kairys A, Williams D, Clauw DJ, Schmidt-Wilcke T. Changes in regional gray matter volume in women with chronic pelvic pain: a voxel-based morphometry study. Pain. 2012 Mar 1. [Epub ahead of print]
To see if changes in the brain’s central pain system have any relation to chronic pelvic pain, researchers at the University of Michigan studied groups of women who had CPP with and without endometriosis. The researchers compared brain images of four subgroups of women: 17 who had endometriosis and CPP, 15 with endometriosis without CPP, six with CPP without endometriosis, and 23 healthy controls (who had neither endometriosis nor CPP). Both groups of women who had CPP, those with endometriosis and those without it, had less gray matter volume in the left thalamus (a brain region involved in pain processing) than women who did not have CPP. The researchers conclude that although endometriosis may be involved in the development of CPP, changes in the brain’s central pain system may also play an important role. As you may recall, investigators of the National Institutes of Health Multidisciplinary Approach to Pelvic Pain Research Network are also looking at changes in the brain in chronic pelvic pain patients—more to come on how these findings match up with that other University of Michigan research group.
Of Mice and Men: The Role of Mast Cells in Male Chronic Pelvic Pain
Done JD, Rudick CN, Quick ML, Schaeffer AJ, Thumbikat P. Roles of mast cells in male chronic pelvic pain. J Urol. 2012 Feb 16. [Epub ahead of print]
Among the many mysteries of chronic pelvic pain is what causes it in 90 percent of the men who have chronic prostatitis. We do know that men with chronic pelvic pain syndrome have increased mast cell tryptase and nerve growth factor in prostate secretions. To find out whether these could be factors causing the pain, researchers at Northwestern University Feinberg School of Medicine studied mice that had experimental autoimmune prostatitis, which is similar to IC. The mice had increased total and activated mast cells and increased nerve growth factor in the prostate. When treated with a combination of a mast cell stabilizer and a histamine 1 receptor antagonist, the mice had a synergistic (the combination worked better than either product alone) decrease in pelvic pain. However, neutralizing the nerve growth factor did not relieve the pain. These results suggest that mast cells are involved in chronic pelvic pain in experimental autoimmune prostatitis. If so, targeting mast cells could have potential for the treatment of men with chronic prostatitis/chronic pelvic pain syndrome.
Pain Susceptibility, Not Nerve Damage, May Predict Chronic Pain after Hysterectomy
Brandsborg B. Pain following hysterectomy: Epidemiological and clinical aspects. Dan Med J. 2012 Jan;59(1):B4374.
Some research has linked IC with hysterectomy, but it’s not known why IC or other chronic pain conditions may start after the procedure. Now, this study offers some clues. In its survey of 1,135 women one year after hysterectomy, 32 percent of women had chronic postoperative pain develop. Risk factors for that outcome were having had pain before surgery, Cesarean section, or other preoperative pain problems. Spinal anesthesia for the surgery reduced the risk. The author also studied a smaller group of patients (90) who filled out questionnaires and underwent tests before their surgery and one and four months after hysterectomy. The surgical approach—abdominal or vaginal—didn’t seem to have any effect on postoperative pain. Risk factors for later pain were high-intensity pain right after surgery and some preoperative pain problems, including allodynia (pain from something not normally painful—in this case, a brush stroke), hyperalgesia (increased sensitivity to pain—in this case, pinpricks), and low thresholds for vaginal pain. Pain susceptibility, and not nerve damage, concluded the author, may explain who gets chronic pain afterward.
Urinary Tract Endometriosis More Common Than Thought
Prevalence and management of urinary tract endometriosis: a clinical case series. Gabriel B, Nassif J, Trompoukis P, Barata S, Wattiez A. Urology. 2011 Dec;78(6):1269-74. Epub 2011 Sep 29. PMID: 21962747
Urinary tract endometriosis can have some of the same symptoms as IC, such as urgency, frequency, and pain with urination. This article indicates that urinary tract endometriosis may be more common than previously thought. That means there may be more potential for misdiagnosis as IC or for IC to be misdiagnosed as urinary tract endometriosis. This review of the records of the 221 patients who had undergone laparoscopy for severe pelvic endometriosis from 2007 to 2010 showed that 43 (19.5 percent) had urinary tract endometriosis. That’s a much larger percentage than the usually estimated 1 to 4 percent. The disease affected the bladder in most of the patients who had urinary tract endometriosis (33 or 77 percent—including 3 patients who had bladder as well as ureteral endometriosis). Patients with bladder endometriosis had more painful urination, blood in the urine, and urinary tract infection than patients who had endometriosis only in the ureters. Most patients (22) were treated with “skinning” of the bladder lining, but 11 patients underwent partial bladder removal. Diagnosing urinary tract endometriosis is a challenge because it doesn’t have specific symptoms, noted the authors. They believe pelvic MRI can be useful for diagnosis.
Mast Cells, Genetics May Be the Major Players in IC Pain
Rudick CN, Pavlov VI, Chen MC, Klumpp DJ. Gender Specific Pelvic Pain Severity in Neurogenic Cystitis. J Urol. 2011 Dec 16. [Epub ahead of print]
Genetics and mast cells, but not hormones, may be the major players in IC pain, shows this study of two different strains of mice with a type of IC induced by a viral infection. ICA Update readers are familiar with this intriguing model of IC that demonstrates nerve, mast cell, and bladder connections from our interview with lab leader David Klumpp, PhD, in the Summer 2011 issue. The researchers looked at how much pain the female and male mice of each strain demonstrated, how much inflammation and lining dysfunction they had in their bladders, and their levels of mast cells. The researchers also looked at whether these things changed with hormonal status when the female mice had ovaries removed and when they had estrogen replacement after that. Female mice of each genetic type showed much more pelvic pain than the male mice, but the female mice of one strain showed significantly more pain than the other. The pain in the female mice didn’t correlate with the degree of bladder inflammation of bladder lining dysfunction, and hormonal manipulation had no effect on pain. The number of mast cells, however, did correlate with the degree of pelvic pain in female mice, but that didn’t correlate with the male-female differences. The research team concluded that the pain depends on gender-specific responsiveness to mast cells. How severe the pain is depends on genetic factors.
IC Patients with Nerve-related Pain Do Worse
Cory L, Harvie HS, Northington G, Malykhina A, Whitmore K, Arya L. Association of Neuropathic Pain With Bladder, Bowel and Catastrophizing Symptoms in Women With Bladder Pain Syndrome. J Urol. 2011 Dec 14. [Epub ahead of print]
IC patients with neuropathic (nerve-related) pain do worse than others, shows this study of 150 women with IC. A little more than a quarter (27 percent) had neuropathic pain. Typical characteristics of neuropathic pain are that it can radiate, come in sharp attacks, or involve hypersensitivity to touch. IC patients with neuropathic pain had significantly worse urinary urgency, bladder pain, bowel pain, diarrhea, and quality of life and higher scores on measures of pain “catastrophizing” or coping than other IC patients.
UTIs Make Bladders Sensitive
Arya LA, Northington GM, Asfaw T, Harvie H, Malykhina A. Evidence of bladder oversensitivity in the absence of an infection in premenopausal women with a history of recurrent urinary tract infections. BJU Int. 2011 Nov 30. doi: 10.1111/j.1464-410X.2011.10766.x. [Epub ahead of print]
Urinary tract infection (UTI) has been implicated in IC, but what the relationship is between the two hasn’t been clear. Some have thought UTIs could trigger IC, and others think bacteria may go into hiding and return periodically to cause symptoms that get diagnosed as IC. This case control study supports the trigger hypothesis, showing that UTIs make the bladder more sensitive. These urogynecologists did some urodynamic studies and analyzed bladder diaries for 59 premenopausal women with recurrent UTIs (with at least three proven UTIs in the previous 12 months and no active infections at the time of the study) as well as 53 control women who did not (who were premenopausal women with stress urinary incontinence and no history of recurrent UTIs or urge incontinence). The women who had recurrent UTIs had significantly more voids per day and voids for the same intake of liquids than the controls. Urodynamics showed that those who had recurrent UTIs also felt a strong desire to void with significantly less urine in their bladder and also had lower bladder capacity than the controls. In addition, the average volume of urine in voids was significantly lower in the women who had had recurrent UTIs than in the controls. This implies that women with recurrent UTIs should be evaluated and treated promptly for their UTIs to reduce the risk of developing IC. Whether women who have recurrent UTIs are truly at increased risk of developing IC in their future needs to be confirmed, said the investigators.
Pelvic Pain May Set Up Patients for More Pain after Pelvic Surgery
Vandenkerkhof EG, Hopman WM, Goldstein DH, Wilson RA, Towheed TE, Lam M, Harrison MB, Reitsma ML, Johnston SL, Medd JD, Gilron I. Impact of Perioperative Pain Intensity, Pain Qualities, and Opioid Use on Chronic Pain After Surgery: A Prospective Cohort Study. Reg Anesth Pain Med. 2011 Dec 6. [Epub ahead of print]
This study looked at what might help predict who will have chronic pain after gynecologic surgery. The researchers looked at the records of 433 women who underwent surgery. Fourteen percent had pain six months later, and 12 percent had pain that interfered with their lives. Twenty-three percent of the women who had pelvic pain before surgery had chronic postsurgical pain afterwards, compared with 17 percent who had remote pain and 5.1 percent who had no pain beforehand. Women were more likely to have chronic postoperative pain or pain that interfered with their lives if they had anxiety or pain before surgery or moderate to severe in-hospital pain. Those who had pelvic pain that was “miserable” or “shooting,” those who took opioids for pain beforehand, and those with pelvic pain and took opioids were also more likely to have chronic postsurgical pain. Pelvic pain, especially severe pelvic pain, may set patients up for more pain after surgery is performed in the pelvic area.
New Twin Study Confirms Genetic Contribution
Tunitsky E, Barber MD, Jeppson PC, Nutter B, Jelovsek JE, Ridgeway B. Bladder Pain Syndrome/Interstitial Cystitis in Twin Sisters. J Urol. 2011 Nov 14. [Epub ahead of print]
These researchers took the opportunity at the famous Twins Day in Twinsburg, Ohio, to ask adult twin sisters about bladder symptoms. The investigators concluded that the genetic factors do contribute to the risk of having IC. A subject was thought likely to have IC based on a score of 13 or more on the O’Leary-Sant Symptom and Problem Indexes. Of the 492 women (246 identical twin sister pairs) who participated in the study, 45 women (9 percent) had moderate to high risk of having IC based on that O’Leary-Sant cutoff, and in 5 twin pairs (2 percent), both likely had IC. The correlation of scores among twins on the questionnaire was 0.35, which suggested a genetic contribution. Increasing age, irritable bowel syndrome, physical abuse (but not sexual or emotional abuse), frequent headaches, multiple drug allergies, and the number of urinary tract infections within in the last year correlated with having IC.
Adhesions Need Prevention Attention
Hirschelmann A, Tchartchian G, Wallwiener M, Hackethal A, De Wilde RL. A review of the problematic adhesion prophylaxis in gynaecological surgery. Arch Gynecol Obstet. 2011 Oct 30. [Epub ahead of print]
Physical therapists often peg adhesions from C sections and other pelvic surgeries as contributors to pelvic pain in IC patients, so wider recognition and prevention could be a boon. Adhesion formation is the most frequent complication in abdominal and pelvic surgery; nevertheless, many surgeons are still not aware of the extent of the problem, said these authors. Surgeons should learn about and use prevention strategies, which include films and gels. The authors call for further research to fully understand how adhesions form, how to prevent them from forming, and which anti-adhesion agents are most effective.
New Key to Pain Intensity Discovered
Emery EC, Young GT, Berrocoso EM, Chen L, McNaughton PA. HCN2 ion channels play a central role in inflammatory and neuropathic pain. Science. 2011 Sep 9;333(6048):1462-6.
Pharmacologists at the University of Cambridge in England have found a new key to how the body senses the intensity of pain with their discovery of the role a member of the HCN ion channel family in neuropathic and inflammatory pain. Mice bred to lack the gene for the HCN2 ion channel had normal pain thresholds, but inflammation did not cause the usual increase in sensitivity to pain from heat. Through this and other experiments, the researchers concluded that neuropathic (nerve-generated) pain is initiated by HCN2 firing in certain pain-sensing nerves. This discovery opens up the possibility of developing specific blockers that could treat neuropathic pain, which is very difficult to do. Some of the pain of IC is thought to be neuropathic.
Tender Point May Talk to Your Bladder
Furuta A, Suzuki Y, Honda M, Koike Y, Naruoka T, Asano K, Chancellor M, Egawa S, Yoshimura N. Time-dependent changes in bladder function and plantar sensitivity in a rat model of fibromyalgia syndrome induced by hydrochloric acid injection into the gluteus. BJU Int. 2011 Aug 2. doi: 10.1111/j.1464-410X.2011.10258.x. [Epub ahead of print]
Treating a gluteus muscle tender point might ease bladder sensitivity, implies this animal study. Knowing that fibromyalgia can accompany IC and that fibromyalgia has specific tender points, these researchers looked at the correlation between muscle pain, specifically gluteal pain, and bladder pain. Under anesthesia, rats got an injection of a small amount of hydrochloric acid into the gluteus muscle, which simulates fibromyalgia, and the control rats got injections of a neutral saline solution. The researchers checked some of the rats’ sensitivity to touch on the hind paw one, two, and three weeks later. Other rats underwent a type of urodynamic testing before and after they got a kind of trigger point treatment with the anesthetic lidocaine injected into the gluteus. One and two weeks later, rats that had the gluteus muscle irritation were much more sensitive to touch on the hind paw than controls. The rats that got the lidocaine treatment injections had much longer times between bladder contractions and much higher volumes of urine voided than the rats that didn’t get the lidocaine treatment. In IC patients with fibromyalgia, bladder sensitivity might result from cross-sensitization between the bladder and the gluteal tender point, so treating the tender point may be effective for frequency, concluded the researchers.
Wipe Out Old Research Options for IC
Cruz F. The Future of Pharmacologic Treatment for Bladder Pain Syndrome/Interstitial Cystitis: Lessons From a Meta-Analysis. Eur Urol. 2011 Sep 28. [Epub ahead of print]
In this commentary on a systematic review of IC treatment, the author calls for new directions in treatment research and sees hope, despite the gloomy picture the review painted. The review, which we summarized last month (“Meta-Analysis Shows No Big IC Winner”) showed that only cyclosporine and amitriptyline demonstrated any consistently great effect on IC in randomized trials. Amitriptyline may not be effective for all, may require larger doses for some, and may have difficult side effects. Cyclosporine treatment also carries side effect risks and can be very costly. Treatment studies, the author pointed out, are of old drugs that have only weak studies to support them. “It is time to wipe out all those old options from the research field and initiate a new period of investigation looking for another set of compounds,” said Dr. Cruz. He thinks pain and bladder inflammation will be the most important targets for new drugs. He believes the most interesting and potentially useful drugs for IC pain are cannabinoid receptor (CB1) agonists (stimulators), TRPV1 (the “hot pepper” receptor) antagonists (blockers), and antagonist (blocker) compounds for the purinergic receptor (the receptor for the sometime pain-transmitting ATP). He also hopes for trials of onabotulinumtoxinA (Botox) that will compare whole-bladder with trigone-only injections, new types of botulinum toxins, gene therapy, more effective anti-inflammatory compounds, and APF-related compounds.
More Focus Needed on Estrogen’s Role
Chaban V. Estrogen and Visceral Nociception at the Level of Primary Sensory Neurons. Pain Res Treat. 2012 Jan 1;2012(2012). pii: 960780.
The co-occurrence of IC and other pain conditions and their high prevalence in women calls for focus on the role of estrogen in the cross-sensitization of visceral organs, this researcher argues. His and his colleagues’ studies suggest that this process may not take place centrally, that is in the brain and spinal cord, but peripherally, at the dorsal root ganglia (the nodules of nerve cells where the front and back nerve roots from the spinal cord come together). Estrogens affect a wide range of nerve functions, including regulating the flow of calcium across membranes (essential for transmitting signals) and regulating purinoreceptors (which ATP activates and which play a role in pain sensation).
Review Highlights Myofacial Component of Pelvic Pain
Díaz-Mohedo E, Barón-López FJ, Pineda-Galán C. Etiological, Diagnostic and Therapeutic Consideration of the Myofascial Component in Chronic Pelvic Pain. Actas Urol Esp. 2011 Sep 12. [Epub ahead of print]
With a systematic review of the medical literature on pelvic pain, these physical medicine specialists concluded that myofascial problems may be responsible for perpetuating symptoms and the lack of resolution of pelvic pain.
Stress Could Prompt Long-lasting Urinary Changes
Smith AL, Leung J, Kun S, Zhang R, Karagiannides I, Raz S, Lee U, Glovatscka V, Pothoulakis C, Bradesi S, Mayer EA, Rodríguez LV. The Effects of Acute and Chronic Psychological Stress on Bladder Function in a Rodent Model. Urology. 2011 Aug 23. [Epub ahead of print]
Stressed rats showed significant increases in frequency, time between voids, and volume as well as increased blood vessel formation and total and activated mast cells in their bladders. The stress was a standard repeated water avoidance test, which was performed for 10 days in a row to model chronic stress. The alterations in voiding persisted for about a month.
Wider May Be Better for Bike Seats
Guess MK, Partin SN, Schrader S, Lowe B, Lacombe J, Reutman S, Wang A, Toennis C, Melman A, Mikhail M, Connell KA. Women’s Bike Seats: A Pressing Matter for Competitive Female Cyclists. J Sex Med. 2011 Aug 11. doi: 10.1111/j.1743-6109.2011.02437.x. [Epub ahead of print]
Women cyclists can develop genital pain, numbness, and swelling of pelvic floor structures from bike riding, similar to the pudendal nerve problems men sometimes have from bike riding. These researchers analyzed genital vibratory thresholds and saddle pressures in 48 healthy, premenopausal, competitive women bicyclists. More than half of the participants (54.8 percent) used traditional saddles, and the remainder (45.2 percent) rode with cut-out saddles. Traditional saddles produced lower perineal pressures than cutout saddles. Saddle design, however, did not affect mean or peak total saddle pressures. Use of wider saddles was associated with lower peak perineal saddle pressure and lower mean total saddle pressure. Cut-out and narrower saddles negatively affect saddle pressures in female cyclists, concluded the investigators. However, they noted, the effects of saddle design on pudendal nerve sensory function were not apparent. Studies following cyclists over the long term to look at the effect of saddle pressure on the pudendal nerve are needed, they said.
Physical Therapists Argue for Relevance of Psychological Factors in Pelvic Pain . . .
Alappattu MJ, Bishop MD. Psychological Factors in Chronic Pelvic Pain in Women: Relevance and Application of the Fear-Avoidance Model of Pain. Phys Ther. 2011 Aug 11. [Epub ahead of print]
These authors discuss the role of psychological variables in chronic pelvic pain in women, especially vulvodynia and IC. Their psychological model is based in the fear-avoidance model (FAM) of pain, which theorizes that some people are more likely to develop and maintain pain after an injury because of their emotional and behavioral responses to it. They divide people into those who have low fear, confront pain, and recover from injury and people who catastrophize pain, which they say leads to avoidance/escape behaviors, disuse, and disability. The authors suggest that physical therapists integrate this model into their decision making, based on the pain-related thinking and behavior of their patients.
. . . But These Doctors Say Psychological Disorders Reflect Pelvic Pain Rather than Prompt It
Roth RS, Punch MR, Bachman JE. Psychological factors and chronic pelvic pain in women: a comparative study with women with chronic migraine headaches. Health Care Women Int. 2011 Aug;32(8):746-61.
Chronic pelvic pain is often attributed to psychogenic cause, note these authors. They conducted a study to determine whether women with chronic pelvic pain have a typical psychologic profile by comparing the pain experience, psychological functioning, and marital/sexual satisfaction of women with chronic pelvic pain with the same in women who had chronic migraine headache. Patients with chronic pelvic pain were more dissatisfied with their marriage and had more sexual dysfunction. But there were no differences between the groups in terms of depression, anxiety, mood factors, or additional personality traits. These data suggest that, in general, when psychological disorders are observed in chronic pelvic pain patients, they most likely reflect the effects of chronic pain rather than cause it, concluded the authors.
Pain Changes the Brain . . .
Farmer MA, Chanda ML, Parks EL, Baliki MN, Apkarian AV, Schaeffer AJ. Brain functional and anatomical changes in chronic prostatitis/chronic pelvic pain syndrome. J Urol. 2011 Jul;186(1):117-24. Epub 2011 May 14.
Functional magnetic resonance imaging showed that the brains of men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) are different from those of healthy men. Compared with 14 healthy men, 19 men with CP/CPPS had higher densities of gray matter in pain-processing brain regions (anterior insula and anterior cingulate cortices). The densities correlated with the intensity of their pain and how long they had had it. In addition, when men with CP/CPPS had pain while they were in the scanner, the researchers could see that the right anterior insula of the brain was activated, and the activation was related to how intense the pain was. Furthermore, in the men with CP/CPPS, the proportions of gray and white brain matter were not stable, unlike in the healthy men. The authors concluded that further research is needed into the central nervous system processes that may start and maintain CP/CPPS.
. . . But Pain Treatment Changes the Brain Back
Seminowicz DA, Wideman TH, Naso L, Hatami-Khoroushahi Z, Fallatah S, Ware MA, Jarzem P, Bushnell MC, Shir Y, Ouellet JA, Stone LS. Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function. J Neurosci. 2011 May 18;31(20):7540-50.
Does chronic pain start in the brain, and does it mean that pain is ingrained there? No, indicates this study of people with chronic low back pain. It’s known that in patients with chronic pain, the brain’s gray matter is reduced and thinking ability is impaired. But when chronic low back pain patients in this study got effective pain treatment, their brains recovered. The researchers got MRI scans before and after spine surgery or facet joint injections in 14 patients and compared the scans with those of 16 healthy controls, including 10 who returned six months later. The investigators looked at the brains’ cortical thickness and activity during a task that demanded a lot of attention. Patients started out with a thinner left dorsolateral prefrontal cortex (DLPFC) than their healthy counterparts, but after treatment, this cortex got thicker. The increased thickness correlated with how much pain and physical disability were reduced. The increase in the thickness of the brain’s primary motor cortex correlated with the reduction in physical disability, and the increase in thickness of the right anterior insula correlated with reduced pain. The activity in the left DLPFC was abnormal before treatment, but was normal after treatment. Treating chronic pain can restore normal brain function in humans, the authors concluded. That’s a message of hope.
Is IC an Autoimmune Disease? New Mouse Model Revives the Idea
Altuntas CZ, Daneshgari F, Sakalar C, Goksoy E, Gulen MF, Kavran M, Qin J, Li X, Tuohy VK. Autoimmunity to Uroplakin II Causes Cystitis in Mice: A Novel Model of Interstitial Cystitis. Eur Urol. 2011 Jun 28. [Epub ahead of print]
Could an autoimmune process cause the defects seen in IC patients’ bladder lining? This experiment points that way. The researchers immunized mice with a recombinant form of a protein called uroplakin II. This protein helps form the top layer of the bladder lining that keeps it locked against urine. The mice had antibody reactions to the recombinant protein and had an IC-like condition develop, with increases in frequency and low-volume voids. The mice also produced more inflammatory cytokines in the bladder lining, but not in other organs. The next step, the researchers said, will be to test the mice for evidence of pain or hypersensitivity and look for actual bladder lining damage.
Pelvic Surgery Prompts Chronic Pelvic Pain, Treatment with Stimulators
Martellucci J, Naldini G, Del Popolo G, Carriero A. Sacral nerve modulation in the treatment of chronic pain after pelvic surgery. Colorectal Dis. 2011 Apr 25. doi: 10.1111/j.1463-1318.2011.02659.x. [Epub ahead of print]
These Italian urologists detail their efforts to ease chronic pelvic pain that developed after pelvic surgery in 17 women. The surgeries the patients had undergone included hysterectomy, surgery to repair or remove hemorrhoids or fistulas, rectal surgery, surgical opening of the urethral sphincter, appendectomy, disk surgery, or laparoscopy for endometriosis. Eight of the patients qualified for a sacral neuromodulator, underwent surgery, and were followed up for a mean of 39 months. Their pain levels fell from an average of 8.2 on a 10-point scale before implantation to,1.9, 2.1, 2.0 and 1.8 at 6, 12, 24 and 36 months. Those who were under age 60 and had had symptoms for less than two years did better, and those who had had stapling did worse.
Rethink Bladder Sensation?
De Wachter SG, Heeringa R, van Koeveringe GA, Gillespie JI. On the nature of bladder sensation: The concept of sensory modulation. Neurourol Urodyn. 2011 Jun 9. doi: 10.1002/nau.21038. [Epub ahead of print]
Could researchers be missing something when it comes to talking about bladder sensation, such as frequency and urgency, and how sensation is affected in IC and other bladder conditions? These urologists and neuroscientists think so, based on their review of the literature about bladder sensation. They believe that there are differences in what might be described as “introspective bladder sensations,” the sensations immediately before voiding, and sensations while voiding. They propose a model that describes how the information from the body that generates the “introspective bladder sensations’ and the voiding sensations themselves might be different but interrelated. More research, such as work with focus groups, is needed to better understand the physiology of bladder sensation and the pathology of increased urgency, frequency, and incontinence, the authors said.
Bladder Sensation Rethought
Heeringa R, de Wachter SG, van Kerrebroeck PE, van Koeveringe GA. Normal bladder sensations in healthy volunteers: A focus group investigation. Neurourol Urodyn. 2011 May 23. doi: 10.1002/nau.21052. [Epub ahead of print]
The same group of researchers that proposed rethinking bladder sensation did some research themselves with a focus group of 11 healthy participants, 4 men and 7 women, who were asked to describe their bladder-related sensations. Before each session, the participants drank a specific, large quantity of water. They all experienced two different types of sensations--“pressure” or “tingling.” The first sensation developed continuously. The terms that described the process of getting to the point where they absolutely had to urinate included “no sensation,” “weak awareness,” “stronger awareness,” “weak need,” “stronger need,” and “absolute need” to void.
Connections Between IC, Associated Conditions, and the Bladder Lining
Birder LA, Hanna-Mitchell AT, Mayer E, Buffington CA. Cystitis, Co-morbid disorders and associated epithelial dysfunction. Neurourol Urodyn. 2011 Jun;30(5):668-72. doi: 10.1002/nau.21109.
This review article tries to pull together what we know about IC, its sometimes-associated conditions, and changes in the bladder lining. The authors point out that a number of syndromes share changes in the barrier function of organ linings and the linings’ signaling functions. Lining cells can respond to a number of challenges, including environmental inputs and mediators of pain or inflammation that are released from nerves or nearby inflammatory cells. These can change the sensitivity of the lining to various substances, allow irritating substances to pass through, or lead to release of substances that may act on nerves or other cells.
Study Points to Biochemical Pathway for Bladder Pain Sensation
Lai HH, Qiu CS, Crock LW, Morales ME, Ness TJ, Gereau RW 4th. Activation of spinal extracellular signal-regulated kinases (ERK) 1/2 is associated with the development of visceral hyperalgesia of the bladder. Pain. 2011 Jun 24. [Epub ahead of print]
These researchers found that two extracellular signal-regulated kinases (ERKs), which are also known as mitogen-activated protein kinases (MAPKs), are important in the development of bladder hypersensitivity. (It was already known that these play a role in body hypersensitivity but not sensitivity of internal organs.) The team correlated an increase in bladder hyperalgesia with enhanced activation of ERK1/2 in the dorsal horn and deeper laminae on both sides of the spinal cord in the sixth lumbar (L6) to first sacral (S1) segments. They also found that blocking ERK1/2 activity with an MEK inhibitor known as U0126 eased bladder pain sensations caused by bladder expansion. This discovery may open another avenue for drug therapy to stop bladder pain.
Chronic Pelvic Pain Correlates with Rheumatic Disease
Driul L, Bertozzi S, Londero AP, Fruscalzo A, Rusalen A, Marchesoni D, Di Benedetto P. Risk factors for chronic pelvic pain in a cohort of primipara and secondipara at one year after delivery: association of chronic pelvic pain with autoimmune pathologies. Minerva Ginecol. 2011 Apr;63(2):181-7.
This study wasn’t about IC per se, but it drew a correlation between chronic pelvic pain (in women who had given birth to one or two children) with some factors we might expect, such as previous pelvic surgery, and one that isn’t commonly thought of—rheumatic disease, such as rheumatoid arthritis. The statistical correlation led the authors to conclude that delivery may highlight chronic pelvic pain symptoms in predisposed women affected by chronic autoimmune disease.
New Study Confirms Common Diet Triggers
Bassaly R, Downes K, Hart S. Dietary Consumption Triggers in Interstitial Cystitis/Bladder Pain Syndrome Patients. Female Pelvic Med Reconstr Surg. 2011;17(1):36-39.
The diet study by University of South Florida researchers that many of you participated in has now been published, and it helps confirm previous studies showing that consumables have an effect on IC symptoms and what the common ones are. Thanks to you, the researchers got 598 complete responses to their web-based questionnaire about the effects of foods, beverages, additives, and supplements. They asked about the effects of 344 different items. Most items had no effect on symptoms. Items that made symptoms worse were citrus fruits, tomatoes, coffee, tea, carbonated and alcoholic beverages, spicy foods, artificial sweeteners, and vitamin C. Only calcium glycerophosphate (Prelief) and sodium bicarbonate (baking soda) showed a trend toward improving symptoms. The results show that IC diets do not have to be overly restrictive, said these researchers.
Tea, Smoking Linked with IC
Tettamanti G, Nyman-Iliadou A, Pedersen NL, Bellocco R, Milsom I, Altman D. Influence of Smoking, Coffee, and Tea Consumption on Bladder Pain Syndrome in Female Twins. Urology. 2011 Mar 23. [Epub ahead of print]
Tea and smoking, but not coffee, show a link with IC in Swedish Twin Study data. That study recently yielded new information about the genetic risk of IC, but part of the Twin Study researchers’ work was also to ask about lifestyle. That information allows analysts to uncover whether certain health or dietary factors are linked with the symptoms or conditions people have. When there is a definite relationship, those factors are considered risk factors for a condition. (That doesn’t mean that these factors cause the condition, but it’s a good guess that changing the factor might change your condition or your chance of getting it.) The study showed that tea drinkers had from one and three quarters (for low tea consumption) to nearly double (for high tea consumption) the chance of having IC symptoms (an Interstitial Cystitis Symptom Index score of 6 or more) than nondrinkers. Former and current smokers had about one and a half times the chance of having symptoms than nonsmokers, although that relationship was not as clear because of family-related factors. There was no significant difference in symptoms between coffee drinkers and coffee abstainers.
Both Pain and Urgency Get You Up at Night
Warren JW, Horne L, Diggs C, Greenberg P, Langenberg PW. Nocturia in interstitial cystitis/painful bladder syndrome. Urology. 2011 Jun;77(6):1308-12.
What wakes you up at night? These researchers asked IC patients directly and also looked at their records from the Events Preceding IC study to find out. Urgency correlated with whether IC patients had nocturia (getting up at night to urinate) and how bad it was. In addition, a large majority of patients said that pain is what wakes them up. Pain may have played an indirect role in nocturia, too, by generating the sensation of urgency. This fits in with the idea that both urinary urgency and bladder pain lead to nighttime voiding in IC patients, concluded the authors.
Is Chronic Pelvic Pain a “Functional Somatic Syndrome”?
Warren JW, Morozov V, Howard FM. Could chronic pelvic pain be a functional somatic syndrome? Am J Obstet Gynecol. 2011 Apr 14. [Epub ahead of print]
These authors, including two IC experts, believe that chronic pelvic pain may be a “functional somatic syndrome.” Those are conditions with no known medical cause. The authors believe that research on these syndromes, including fibromyalgia and irritable bowel syndrome, and research on chronic pelvic pain are coming together to reveal some cause that is primarily outside the pelvis.
IC and Vulvodynia Overlap for Many Patients
Gardella B, Porru D, Nappi RE, Daccò MD, Chiesa A, Spinillo A. Interstitial Cystitis is Associated with Vulvodynia and Sexual Dysfunction-A Case-Control Study. J Sex Med. 2011 Apr 7. [Epub ahead of print]
Some ninety-eight percent of the 47 women with IC in this study had a form of vulvodynia. (IC was diagnosed by older, stricter NIDDK research criteria.) All were patients of the pelvic pain service of the gynecology department at the University of Pavia in Italy and had their IC come on recently—between 6 and 12 months before the study. The clinicians there compared the IC patients with 188 age-matched, healthy controls. Analysis showed that, among the women with IC, 23 percent had spontaneous vulvodynia (vulvar pain that can occur even without touching or pressing) and 74 percent had provoked vulvodynia (vulvar pain with touch), whereas none of the control women had these vulvar pains. In addition, vulvodynia was localized (around the vaginal opening) in 81 percent of the women with IC and more general in a much smaller percentage (17%). Also, 87 percent of the women with IC had pain with intercourse, whereas only 6 percent of the control women did. Vaginal health scores (based on things such as elasticity, intact lining, and moisture) were also significantly lower in IC patients, and patients were also more likely to have mixed vaginal infections and yeast overgrowth. Compared with their healthy sisters, the women with IC were also more likely to be in menopause, to have used or to be using oral contraceptives, or to have confirmed endometriosis. The authors agree with the idea that IC and vulvodynia may have a common cause and speculated that it may be sex-hormone related.
Hot Pepper Receptors Called Culprits in Colon-Bladder Crosstalk
Asfaw TS, Hypolite JA, Northington GM, Arya LA, Wein AJ, Malykhina AP. Acute colonic inflammation triggers detrusor instability via activation of TRPV1 receptors in a rat model of pelvic organ cross-sensitization. Am J Physiol Regul Integr Comp Physiol. 2011 Apr 6. [Epub ahead of print]
Irritating the colon in rats with a hot-pepper-like substance increased bladder contractions and decreased bladder capacity and voided volume, found this research team. But there were differences in the response when only tissue was tested. The results suggest that inflammation of the colon triggers bladder muscle instability through the hot-pepper-like receptor and that intact nerve pathways are required for that to happen. The study adds more evidence to the idea that there is nerve crosstalk between the colon and bladder and that irritation of the colon can lead to bladder symptoms by this route.
Bladder Interstitial Cells May Hold New Treatment Keys
McCloskey KD. Interstitial cells and bladder pathophysiology—passive bystanders or active participants? J Urol. 2011 May;185(5):1562-3. Epub 2011 Mar 21.
The “I” in IC stands for “interstitial,” but it hasn’t been clear what role cells in the bladder’s interstitium might play. Research to find that out is accelerating, demonstrates this author. Studies of subtypes of these cells show they may contribute to the complex cellular signaling within the bladder wall that is responsible for normal bladder function. These cells may also transmit signals from the bladder lining to other cells in the bladder wall, play a role in transmitting sensation as the bladder wall stretches when the bladder fills, and may function as “pacemakers” for the bladder muscle or regulate the muscle’s spontaneous muscle activity. All those processes are thought to play a role in IC. Moreover, the interstitial cells that occur under the bladder lining in IC patients have been shown to take on the character of connective tissue. Changes in the numbers of these cells have a clear relationship with abnormal bladder function, implying that they play an important role in bladder function and could be new treatment targets.
Membrane Protein May Play Role in IC
Lin XC, Zhang QH, Zhou P, Zhou ZS, Lu GS. Caveolin-1 May Participate in the Pathogenesis of Bladder Pain Syndrome/ Interstitial Cystitis. Urol Int. 2011 Feb 19. [Epub ahead of print]
Caveolin-1 is an important protein in the structure of cell membranes, and this research team found that its expression in urine and bladder tissue is much higher in IC patients than in healthy controls. That suggests it may play a role in the disease process.
Which Comes First, the Chicken or IC?
Warren JW, Wesselmann U, Morozov V, Langenberg PW. Numbers and types of nonbladder syndromes as risk factors for interstitial cystitis/painful bladder syndrome. Urology. 2011 Feb;77(2):313-9.
Do other “syndromes” that patients have before IC kick off the IC, or does IC arise out of the same process that causes the other conditions? That remains to be tested, but the idea that this is something to test comes out of the Events Preceding IC (EPIC) study, which found that many IC-associated conditions start before IC. This analysis shows that, in patients who didn’t have many other associated conditions, allergy was very common. (Allergy is not usually considered to be a syndrome.) In patients who had a lot of “functional somatic syndromes,” fibromyalgia, chronic fatigue syndrome, and irritable bowel syndrome were common.
Avoid Adhesions, Contributors to Pelvic Pain
Mais V, Angioli R, Coccia E, Fagotti A, Landi S, Melis GB, Pellicano M, Scambia G, Zupi E, Angioni S, Arena S, Corona R, Fanfani F, Nappi C. Prevention of postoperative abdominal adhesions in gynecological surgery. Consensus paper of an Italian gynecologists’ task force on adhesions. [Article in Italian] Minerva Ginecol. 2011 Feb;63(1):47-70.
This task force of Italian urologists developed a consensus on avoiding and resolving adhesions, a frequent complication of abdominal and pelvic surgery that can cause important short- and long-term problems, including infertility, chronic pelvic pain, a lifetime risk of small bowel obstruction, and complications in future surgeries. They pose serious quality of life issues for many patients, which can increase social and healthcare costs. Surgeons can take important steps to reduce the impact of adhesions, and the task force made practical proposals for actions that gynecologic surgeons in Italy should take. Improvements in surgical technique, developments in adhesion-reduction strategies, and new agents offer a realistic possibility of reducing adhesion formation and improving outcomes for patients, the gynecologists said. They also said patients need to be better informed about the risks of adhesions.
Caution on Ketamine
Wood D, Cottrell A, Baker SC, Southgate J, Harris M, Fulford S, Woodhouse C, Gillatt D. Recreational ketamine: from pleasure to pain. BJU Int. 2011 Feb 14. [Epub ahead of print]
This review article looks at what we’ve learned so far about ketamine abuse and the damage it can do to the bladder. Symptoms include a small painful bladder, obstructed ureters, kidney damage, and liver dysfunction. Bladder inflammation and ulceration have also been reported. Ketamine-induced bladder damage can appear similar to IC. The treatment includes stopping ketamine use and using adequate pain control to overcome symptoms, said the authors. Although some IC patients may be mistakenly thought to be ketamine abusers when they go for help, this recommendation for adequate pain control to overcome symptoms is a positive development, since that should be the case for IC patients as well. Ketamine, however, remains a safe and effective drug to use under appropriate medical supervision, said the authors.
Interstitial Cells Are Different in IC Bladders
Gevaert T, De Vos R, Everaerts W, Libbrecht L, Van Der Aa F, van den Oord J, Roskams T, De Ridder D. Characterization of upper lamina propria interstitial cells in bladders from patients with neurogenic detrusor overactivity and bladder pain syndrome. J Cell Mol Med. 2011 Jan 20. [Epub ahead of print]
These pathologists found that interstitial cells in bladders of patients with IC and in patients with neurogenic detrusor overactivity (the bladder spasms that can occur in spinal cord injury patients) do look different from normal interstitial cells. They shift toward a “fibroblast type,” a cell that is common in connective tissue. The investigators looked at these cells in the lamina propria, which is the layer between the bladder muscle and the bladder lining, because the terminology for that layer still isn’t settled and more remains to be known about the cells’ morphology and immunohistochemistry. Cells from the upper lamina propria in both sets of patients had a fibroblast-like appearance and an immunohistochemistry that put the cells into the category of Cajal-like cells (which may have a pacemaker function). This shift in cell type was more pronounced in the patients with neurogenic detrusor overactivity than in IC patients.
Inflammation Marker Levels Are High in IC and OAB
Chung SD, Liu HT, Lin H, Kuo HC. Elevation of serum C-reactive protein in patients with OAB and IC/BPS implies chronic inflammation in the urinary bladder. Neurourol Urodyn. 2011 Jan 31. [Epub ahead of print]
C-reactive protein (CRP) is a marker of chronic inflammation, and both IC and overactive bladder (OAB) patients have high levels, indicating that inflammation plays a role. These researchers measured serum levels of the marker in 48 IC patients, 22 OAB patients, and 33 controls. Levels were significantly higher in IC and OAB patients than in controls, but there was no significant difference in the levels between IC and OAB patients. The levels of CRP and levels of nerve growth factor in urine were related only in OAB patients who had fairly high CRP levels. The results help demonstrate that the bladder is chronically inflamed in IC and OAB patients, the authors concluded.
Hormones, Pregnancy, Other Chronic Conditions Show Strong Relationship with IC
Explanations remain unclear
Warren JW, Clauw DJ, Wesselmann U, Langenberg PW, Howard FM, Morozov V. Sexuality and Reproductive Risk Factors for Interstitial Cystitis/Painful Bladder Syndrome in Women. Urology. 2011 Jan 6. [Epub ahead of print]
These researchers found associations between IC and three characteristics that came before the diagnosis: hormone use, having had fewer pregnancies (for still-cycling women), and associated conditions, such as allergies, irritable bowel syndrome (IBS), and fibromyalgia. The associated conditions had the strongest relationship with IC, especially as the number went up. The associated conditions that IC patients had most often compared with controls were “chronic pelvic pain,” irritable bowel syndrome, and panic disorder. The odds were also higher that IC patients had used noncontraceptive female hormones and had undergone an abortion. Also, women with IC were less likely to have been pregnant.
Why these things are risk factors for IC isn’t clear. Don’t take these results to mean that hormone use and abortion cause IC or that pregnancy prevents it. It could be that the women who used noncontraceptive hormones were taking them to help treat pelvic pain. Oral contraceptives are a typical treatment for endometriosis, which many IC patients have, but it was not mentioned specifically in the article. It may have fallen under the category of chronic pelvic pain, especially if it had gone undiagnosed, which is common. Although the authors speculated that hormones at and after menopause might play a role in encouraging the development of IC and that hormones might enhance pain, the relationship might have showed up because postmenopausal women were receiving hormones improve IC symptoms or those that exacerbate IC. Furthermore, studies about estrogen’s effect on pain are conflicting. Women with IC who had abortions may have gone through fewer pregnancies, which the authors speculated might postpone IC. On the other hand, the women may have terminated pregnancy because it was too difficult and painful with their IC and associated conditions. Women with IC may have had fewer pregnancies for similar reasons.
With regard to associated conditions, the authors said finding a cause of these often “functional syndromes” would likely also help reveal the cause of IC. The functional syndromes, which are groups of symptoms that have no apparent physical cause, are now often thought to result from abnormal brain processing of sensory information. Research, however, is suggesting potential causes outside of the nervous system for some of these disorders, such as viruses in chronic fatigue syndrome and chronic low-grade chronic inflammation in IBS.
Plethora of Pelvic Pains Pegged as IC
Parsons CL. The role of a leaky epithelium and potassium in the generation of bladder symptoms in interstitial cystitis/overactive bladder, urethral syndrome, prostatitis and gynaecological chronic pelvic pain. BJU Int. 2010 Dec 22. doi: 10.1111/j.1464-410X.2010.09843.x. [Epub ahead of print]
This researcher argues that early IC is often misdiagnosed as urinary tract infection, urethral syndrome, overactive bladder, chronic prostatitis, urethritis, or some type of gynecologic pelvic pain (endometriosis, vulvodynia, or another vaginitis) and that they are all really the same bladder disease. He believes that the disease, which he calls lower urinary dysfunction epithelium (LUDE), results from a leaky bladder lining, which allows potassium to leak through the bladder lining to generate symptoms.
IC Recognized as Source of Cyclic Pelvic Pain
Won HR, Abbott J. Optimal management of chronic cyclical pelvic pain: an evidence-based and pragmatic approach. Int J Womens Health. 2010 Aug 20;2:263-77.
Pelvic pain related to the menstrual cycle is common, yet there’s not much high-quality evidence on how to manage it. These analysts combed through the medical literature for articles about cyclic pain. They said the literature indicates that chronic pelvic pain affects from 4 to 25 percent of reproductive-age women, and menstrual pain of varying degrees affects 60 percent of women. Endometriosis came up as the most common cause of cyclic pelvic pain. Other gynecologic causes include adenomyosis, uterine fibroids, and pelvic floor myalgia. But the authors noted that disease in other systems, such as irritable bowel syndrome or IC, may also be responsible. Options for treatment range from the simple to invasive, but the authors called the combined oral contraceptive pill a first-line option before more invasive treatments. Doctors need to take careful histories, do careful physical examinations, and consider appropriate tests to identify the cause or causes of the pain and decide on the optimal treatment, concluded the authors.
Migraines Common in Women with Pelvic Pain
Karp BI, Sinaii N, Nieman LK, Silberstein SD, Stratton P. Migraine in women with chronic pelvic pain with and without endometriosis. Fertil Steril. 2010 Dec 8. [Epub ahead of print]
Among 108 women in a clinical trial for chronic pelvic pain, 67 percent had definite or probable migraine headaches at some time in their lives. Another eight percent had “possible” migraine. Migraine was no more likely in women who had endometriosis than in those without endometriosis. Women with the most severe headaches had a lower quality of life than those with pelvic pain alone. The authors said these findings indicate, not only that migraine contributes to disability in women with pelvic pain, but also that there may be a common origin for migraine and chronic pelvic pain.
Brüggmann D, Tchartchian G, Wallwiener M, Münstedt K, Tinneberg HR, Hackethal A. Intra-abdominal adhesions: definition, origin, significance in surgical practice, and treatment options. Dtsch Arztebl Int. 2010 Nov;107(44):769-75. Epub 2010 Nov 5.
Adhesions after surgery in the abdominal cavity can lead to or aggravate pelvic pain. They are common, but surgeons can take measures to avoid them. This article tells them how and encourages them to take these precautions. Adhesions are areas of scar tissue that form after surgery or other wounds in the abdominal cavity and attach normally separated organs to each other. Adhesions can result in bowel obstruction, chronic pelvic pain, painful sex, infertility, and higher rates of complications in subsequent surgery. Surgeries that carry the highest risk of adhesion formation are on the ovaries or bowel. Adhesions are almost inevitable, arising after more than 50 percent of all abdominal operations. Nevertheless, the authors emphasized, it’s important for surgeons to avoid them by minimizing injury during surgery, keeping the lining of the body cavity moist, irrigating the cavity during surgery to remove blood and clots, and using a minimum of foreign material in the abdomen.
Pelvic Floor-Back Pain Relationship Explored
Mohseni-Bandpei MA, Rahmani N, Behtash H, Karimloo M. The effect of pelvic floor muscle exercise on women with chronic non-specific low back pain. J Bodyw Mov Ther. 2011 Jan;15(1):75-81. Epub 2009 Dec 28.
Low back pain may be fairly common in IC patients and is recognized as a symptom of pelvic floor dysfunction. That’s why these physical therapists tried pelvic muscle training to see if it would help resolve low back pain. In a controlled clinical trial in 20 women with chronic low back pain, they tried routine treatment or routine treatment plus pelvic floor exercise. The group that did pelvic floor exercise did no better than the other group. That doesn’t mean that the two are not related, however, since the problems may also go in the other direction—from low back pain to the pelvic floor. In addition, the exercise the therapists used seemed to be aimed at strengthening the pelvic floor muscles rather than relaxing them.
DMSO Interferes with Inflammation
Kim R, Liu W, Chen X, Kreder KJ, Luo Y. Intravesical dimethyl sulfoxide inhibits acute and chronic bladder inflammation in transgenic experimental autoimmune cystitis models. J Biomed Biotechnol. 2011;2011:937061. Epub 2010 Nov 11.
Using a new strain of mice that have IC characteristics, these researchers looked into the effects of dimethyl sulfoxide (DMSO) on bladder tissue and physiology. The mice with the IC-like condition that got DMSO showed less tissue damage and had more genetic expression of inflammatory factors. DMSO also inhibited bladder inflammation in other mice that had a kind of chronic cystitis and impaired immune cells, called effector T cells, in direct relationship to the amount of DMSO used.
Bacteria May Kick Off Pelvic Pain
Rudick CN, Berry RE, Johnson JR, Johnston B, Klumpp DJ, Schaeffer AJ, Thumbikat P. Uropathogenic E. coli induces chronic pelvic pain. Infect Immun. 2010 Nov 15. [Epub ahead of print]
This study implicating bacteria in setting off the chronic pain of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) hints that this may be at work in IC as well. In this study, the researchers took a strain of infectious Escherichia coli bacteria from a man with CP/CPPS and injected it into a particular strain of mice that develop a kind of autoimmune prostatitis. This bacterial strain was not typical of most E coli in urinary tract infections. In addition, the bacteria adhered to, invaded, and proliferated within the prostate lining and colonized both the prostate and bladder of the prostatitis-prone mice. The mice showed sustained and chronic pelvic pain behavior, something that didn’t happen when they were injected with a more common cystitis strain of E coli. The effects continued even after the bacteria were cleared from the tissue. Another common strain of lab mouse did not show these effects after infection. The authors concluded that infection can initiate chronic pelvic pain through processes that depend on both the virulence of the bacterial strain and the genetic background of the host.
Muscle Pain, Symptoms Related in IC
Bassaly R, Tidwell N, Bertolino S, Hoyte L, Downes K, Hart S. Myofascial pain and pelvic floor dysfunction in patients with interstitial cystitis. Int Urogynecol J Pelvic Floor Dysfunct. 2010 Oct 26. [Epub ahead of print]
Myofascial pain has a relationship with pelvic floor dysfunction in patients with IC. These researchers analyzed patient records and found a correlation among myofascial pain, muscle trigger points, scores on the Pelvic Pain and Urgency/Frequency (PUF) questionnaire, and scores on questionnaires related to pelvic floor dysfunction. Among patients with one muscle trigger point, some 78 percent had myofascial pain. A high proportion of patients (68 percent) also had numerous trigger points. The investigators said that these findings help bolster the idea that pelvic floor myofascial pain should be looked at in IC patients and that pelvic floor therapy can help.
Could Altered Bacteria Play a Role in IC?
Domingue GJ. Demystifying pleomorphic forms in persistence and expression of disease: Are they bacteria, and is peptidoglycan the solution? Discov Med. 2010 Sep;10(52):234-46.
This article speculates that “L forms” of bacteria might play a role in a number of disorders we don’t understand, such as chronic inflammatory disorders, collagen disorders, lymphoproliferative disorders, tumors, and IC and chronic prostatitis/chronic pelvic pain syndrome. Although some think that, under the microscope, these “bacteria” may be just staining artifacts or debris, they might be cell-wall-deficient/defective bacteria that are difficult to culture or can’t be cultured. The author said that recent provocative studies lend credence to that idea. These studies have found that many different bacterial forms develop during the reproduction of L forms in the laboratory, that stressed bacteria show different modes of division, that gene expression is modified, and that the forms contain peptidoglycan, a component of bacterial cell walls.
Nurse Speculates on Connection with “Cuddle Hormone” Upset
Seng JS. Posttraumatic oxytocin dysregulation: is it a link among posttraumatic self disorders, posttraumatic stress disorder, and pelvic visceral dysregulation conditions in women? J Trauma Dissociation. 2010 Oct;11(4):387-406.
This article speculates that in women with pelvic pain disorders, “posttraumatic self disorders,” or posttraumatic stress disorder, the hormone oxytocin is out of whack. Although both men and women produce this hormone, dubbed the “cuddle hormone,” it plays a much larger role in women, especially in reproduction, although it is also linked to behavior, such as bonding and reduced anxiety. The author said this theory could account for the greater prevalence of these disorders in women. However, our ideas about the prevalence of IC and pelvic disorders are changing as we find that more men have these disorders than previously thought. In addition, the idea of a common cause links pelvic pain with psychologic disorders, which does not have a strong research foundation.
Study Estimates Overlapping Condition Rates in IC
Nickel JC, Tripp DA, Pontari M, Moldwin R, Mayer R, Carr LK, Doggweiler R, Yang CC, Mishra N, Nordling J. Interstitial cystitis/painful bladder syndrome and associated medical conditions with an emphasis on irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome. J Urol. 2010 Oct;184(4):1358-63. Epub 2010 Aug 17.
Based on 205 IC patients’ own reports, 38.6 percent have irritable bowel syndrome (IBS), 17.7 percent have fibromyalgia, and 9.5 percent have chronic fatigue syndrome. Those rates are higher than the 117 matched control patients’ reports: 5.2 percent said they had IBS, 2.5 percent fibromyalgia, and 1.7 percent chronic fatigue syndrome. Among the IC patients, 50.3 percent reported no other associated condition, 24.4 percent had IC and IBS only, 2.5% had IC and fibromyalgia only, and 1.5 had IC and chronic fatigue syndrome only, whereas 20.2 percent had multiple associated conditions. As the number of associated conditions increased, pain, stress, depression and sleep disturbance increased, while social support, sexual functioning and quality of life deteriorated. It remains to be proven that IC progresses over time from an organ-based condition to a regional and ultimately whole-body condition with worsening symptoms.
Mast Cells, Bladder Lining Problems Don’t Jibe
Geurts N, Van Dyck J, Wyndaele JJ. Bladder pain syndrome: do the different morphological and cystoscopic features correlate? Scand J Urol Nephrol. 2010 Sep 17. [Epub ahead of print]
Patients with IC may have bladder lining damage, such as Hunner’s lesions, and lots of mast cells in the bladder muscle, but not both. There are likely different mechanisms of disease at work, and that is also a reason to do both cystoscopy with hydrodistention and biopsy, which is recommended by European urologists. Doing both studies is recommended by the European Society for the Study of IC (ESSIC, which has changed its name to the International Society for the Study of Bladder Pain Syndrome). The Dutch urologists who did the study did both procedures on 15 men and 39 women. They found that damage to the bladder lining correlated with the infiltration of inflammatory cells. When patients had normal bladder linings, they were much more likely to have proliferation of mast cells in their detrusor muscle than those who had damaged bladder linings. Whether this finding has any bearing on treatment remains to be seen.
Proteins, Pathways Differ in IC
Goo YA, Tsai YS, Liu AY, Goodlett DR, Yang CC. Urinary proteomics evaluation in interstitial cystitis/painful bladder syndrome: a pilot study. Int Braz J Urol. 2010 Jul-Aug;36(4):464-78; discussion 478-9, 479.
This in-depth look at the proteins in IC patients urine found differences from healthy people that may not only provide markers but also some insight into the disease process. When the researchers analyzed urine samples from 10 women with IC and 10 healthy women with proteomics techniques, they found that all the IC patients had alpha-1B-glycoprotein (A1BG) and orosomucoid-1 (ORM1), and 60 percent or more of the patients had higher levels of these two proteins than controls. On the other hand, all the controls had transthyretin (TTR) and hemopexin (HPX), but 60 percent or more of the IC patients had low levels of these two proteins. A process called enrichment functional analysis showed that IC patients’ cells’ ability to adhere and respond to stimuli were lower and their response to inflammation, wounding, and tissue degradation were higher in IC pateints than in controls. In addition, said the authors, activation of neurophysiological processes involved in nerve signal transmission and a lack of DNA damage repair may also be key components of IC.
Unusual IC Case Hints at Autoimmunity
Pacella M, Varca V, Venzano F, Toncini C, Carmignani G, Simonato A. Interstitial cystitis with plasma cell bladder infiltration: case report and literature review. Arch Ital Urol Androl. 2010 Jun;82(2):122-4.
This report describes a case of IC in a patient with “overactive bladder” whose bladder wall was infiltrated with plasma cells. The author noted that only one similar case has been published on. This patient also had perinuclear antineutrophil cytoplasmic antibodies (p-ANCA), implying an autoimmune cause of her condition. The 76-year-old woman got some benefit from corticosteroid therapy, but had to discontinue because of side effects. Her condition worsened t the point where she had a cystectomy and a neobladder.